Skip to main content

Advertisement

SpringerLink
Log in

H2S probe CPC inhibits autophagy and promotes apoptosis by inhibiting glutathionylation of Keap1 at Cys434

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

H2S is actual an endogenous signaling gas molecule and involved in a range of cell physiological processes. However, the mechanism of endogenous H2S regulating autophagy and apoptosis has not been thoroughly investigated. Here, we try to address this issue by using a H2S probe, (E)-2-(4-(4-(7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl)-piperazin-1-yl)-styryl)-1, 3, 3-trimethyl-3H-indol-1-ium iodide (CPC), which could react with endogenous H2S. Herein, we reported that CPC inhibited autophagy and decreased the expression and activity of NF-E2-related factor 2 (Nrf2), then induced cell apoptosis. CPC inhibited autophagy and promoted apoptosis by inhibiting Nrf2 activation, which was H2S dependent. Furthermore, we found that CPC inhibited Nrf2 nucleus translocation by inhibiting glutathionylation of Kelch-like ECH-associated protein 1 (Keap1) at the Cys434 residue. CPC also inhibited various cancer cell growth, but had no effect on normal cell growth in vitro, and inhibited A549 cancer growth, but did not affect normal angiogenesis in vivo. Therefore, we not only found a new inhibitor of autophagy and Nrf2, but also suggested a novel mechanism that endogenous H2S could regulate autophagy, apoptosis and Nrf2 activity through regulating glutathionylation of Keap1 at the Cys434 residue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

Abbreviations

H2S:

Hydrogen sulfide

CPC:

(E)-2-(4-(4-(7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl)-piperazin-1-yl)-styryl)-1, 3, 3-trimethyl-3H-indol-1-ium iodide

Nrf2:

Nuclear factor erythroid 2-related factor 2

Keap1:

Kelch-like ECH associated protein-1

DMSO:

Dimethylsulfoxide

5-FU:

5-Fluorouracil

SRB:

Sulforhodamine B

CCK-8:

Cell counting kit-8

MTS:

3-(4, 5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

PARP:

Poly(ADP-ribose) polymerase

LDH:

Lactate dehydrogenase

MAP1LC3B:

Microtubule associated protein 1 light chain 3 beta

ATG:

Autophagy associated gene

TUNEL:

Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling

CAM:

Chorioallantoic membrane model

TBST:

Tris-buffered saline containing 1% Tween 20

PBS:

Phosphate-buffered saline

References

  1. Mukhopadhyay S, Panda PK, Sinha N, Das DN, Bhutia SK (2014) Autophagy and apoptosis: where do they meet? Apoptosis 19(4):555–566. https://doi.org/10.1007/s10495-014-0967-2

    Article  CAS  PubMed  Google Scholar 

  2. Santiago-O’Farrill JM, Weroha SJ, Hou X, Oberg AL, Heinzen EP, Maurer MJ, Pang L, Rask P, Amaravadi RK, Becker SE, Romero I, Rubio MJ, Matias-Guiu X, Santacana M, Llombart-Cussac A, Poveda A, Lu Z, Bast RC Jr (2019) Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy-mediated drug resistance in ovarian cancer cells, xenografts, and patient-derived xenograft models. Cancer. https://doi.org/10.1002/cncr.32600

    Article  PubMed  Google Scholar 

  3. Szabo C, Coletta C, Chao C, Modis K, Szczesny B, Papapetropoulos A, Hellmich MR (2013) Tumor-derived hydrogen sulfide, produced by cystathionine-beta-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA 110(30):12474–12479. https://doi.org/10.1073/pnas.1306241110

    Article  PubMed  PubMed Central  Google Scholar 

  4. Shen Y, Shen Z, Luo S, Guo W, Zhu YZ (2015) The cardioprotective effects of hydrogen sulfide in heart diseases: from molecular mechanisms to therapeutic potential. Oxid Med Cell Longev 2015:925167. https://doi.org/10.1155/2015/925167

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yang CT, Wang Y, Marutani E, Ida T, Ni X, Xu S, Chen W, Zhang H, Akaike T, Ichinose F, Xian M (2019) Data-driven identification of hydrogen sulfide scavengers. Angew Chem 58(32):10898–10902. https://doi.org/10.1002/anie.201905580

    Article  CAS  Google Scholar 

  6. Yamagishi K, Onuma K, Chiba Y, Yagi S, Aoki S, Sato T, Sugawara Y, Hosoya N, Saeki Y, Takahashi M, Fuji M, Ohsaka T, Okajima T, Akita K, Suzuki T, Senawongse P, Urushiyama A, Kawai K, Shoun H, Ishii Y, Ishikawa H, Sugiyama S, Nakajima M, Tsuboi M, Yamanaka T (2012) Generation of gaseous sulfur-containing compounds in tumour tissue and suppression of gas diffusion as an antitumour treatment. Gut 61(4):554–561. https://doi.org/10.1136/gutjnl-2011-300721

    Article  CAS  PubMed  Google Scholar 

  7. Modis K, Coletta C, Erdelyi K, Papapetropoulos A, Szabo C (2013) Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J 27(2):601–611. https://doi.org/10.1096/fj.12-216507

    Article  CAS  PubMed  Google Scholar 

  8. Feng X, Zhang T, Liu JT, Miao JY, Zhao BX (2016) A new ratiometric fluorescent probe for rapid, sensitive and selective detection of endogenous hydrogen sulfide in mitochondria. Chem Commun 52(15):3131–3134. https://doi.org/10.1039/c5cc09267a

    Article  CAS  Google Scholar 

  9. Lo SC, Hannink M (2008) PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res 314(8):1789–1803. https://doi.org/10.1016/j.yexcr.2008.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. O’Mealey GB, Plafker KS, Berry WL, Janknecht R, Chan JY, Plafker SM (2017) A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J Cell Sci 130(20):3467–3480. https://doi.org/10.1242/jcs.203216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 101(7):2040–2045. https://doi.org/10.1073/pnas.0307301101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rojo de la Vega M, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34(1):21–43. https://doi.org/10.1016/j.ccell.2018.03.022

    Article  CAS  PubMed  Google Scholar 

  13. Gorelenkova Miller O, Mieyal JJ (2015) Sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases. Arch Toxicol 89(9):1439–1467. https://doi.org/10.1007/s00204-015-1496-7

    Article  CAS  PubMed  Google Scholar 

  14. Holland R, Hawkins AE, Eggler AL, Mesecar AD, Fabris D, Fishbein JC (2008) Prospective type 1 and type 2 disulfides of Keap1 protein. Chem Res Toxicol 21(10):2051–2060. https://doi.org/10.1021/tx800226m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Carvalho AN, Marques C, Guedes RC, Castro-Caldas M, Rodrigues E, van Horssen J, Gama MJ (2016) S-Glutathionylation of Keap1: a new role for glutathione S-transferase pi in neuronal protection. FEBS Lett 590(10):1455–1466. https://doi.org/10.1002/1873-3468.12177

    Article  CAS  PubMed  Google Scholar 

  16. Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, Pass HI, Bhutkar AJ, Tsirigos A, Ueberheide B, Sayin VI, Papagiannakopoulos T, Pagano M (2019) Nrf2 Activation promotes lung cancer metastasis by inhibiting the degradation of bach1. Cell. https://doi.org/10.1016/j.cell.2019.06.003

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, Ziegler DV, Xu X, Ghosh T, Mondal T, Kanduri C, Lindahl P, Sayin VI, Bergo MO (2019) BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell. https://doi.org/10.1016/j.cell.2019.06.005

    Article  PubMed  Google Scholar 

  18. Dodson M, Redmann M, Rajasekaran NS, Darley-Usmar V, Zhang J (2015) KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 469(3):347–355. https://doi.org/10.1042/BJ20150568

    Article  CAS  PubMed  Google Scholar 

  19. Navarro-Yepes J, Burns M, Anandhan A, Khalimonchuk O, del Razo LM, Quintanilla-Vega B, Pappa A, Panayiotidis MI, Franco R (2014) Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid Redox Signal 21(1):66–85. https://doi.org/10.1089/ars.2014.5837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pajares M, Cuadrado A, Rojo AI (2017) Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biol 11:543–553. https://doi.org/10.1016/j.redox.2017.01.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xu D, Xu M, Jeong S, Qian Y, Wu H, Xia Q, Kong X (2018) The role of Nrf2 in liver disease: novel molecular mechanisms and therapeutic approaches. Front Pharmacol 9:1428. https://doi.org/10.3389/fphar.2018.01428

    Article  CAS  PubMed  Google Scholar 

  22. Wang J, Liu Z, Hu T, Han L, Yu S, Yao Y, Ruan Z, Tian T, Huang T, Wang M, Jing L, Nan K, Liang X (2017) Nrf2 promotes progression of non-small cell lung cancer through activating autophagy. Cell Cycle 16(11):1053–1062. https://doi.org/10.1080/15384101.2017.1312224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Panieri E, Saso L (2019) Potential applications of NRF2 inhibitors in cancer therapy. Oxid Med Cell Longev 2019:8592348. https://doi.org/10.1155/2019/8592348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Furfaro AL, Traverso N, Domenicotti C, Piras S, Moretta L, Marinari UM, Pronzato MA, Nitti M (2016) The Nrf2/HO-1 axis in cancer cell growth and chemoresistance. Oxid Med Cell Longev 2016:1958174. https://doi.org/10.1155/2016/1958174

    Article  CAS  PubMed  Google Scholar 

  25. Tang M, Ji C, Pallo S, Rahman I, Johnson GVW (2018) Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner. Neurobiol Aging 63:128–139. https://doi.org/10.1016/j.neurobiolaging.2017.12.001

    Article  CAS  PubMed  Google Scholar 

  26. Raghunath A, Sundarraj K, Arfuso F, Sethi G, Perumal E (2018) Dysregulation of Nrf2 in hepatocellular carcinoma: role in cancer progression and chemoresistance. Cancers 10(12):481. https://doi.org/10.3390/cancers10120481

    Article  CAS  PubMed Central  Google Scholar 

  27. Taguchi K, Yamamoto M (2017) The KEAP1-NRF2 system in cancer. Front Oncol 7:85. https://doi.org/10.3389/fonc.2017.00085

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tuo L, Xiang J, Pan X, Gao Q, Zhang G, Yang Y, Liang L, Xia J, Wang K, Tang N (2018) PCK1 downregulation promotes TXNRD1 expression and hepatoma cell growth via the nrf2/keap1 pathway. Front Oncol 8:611. https://doi.org/10.3389/fonc.2018.00611

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhang B, Ma Z, Tan B, Lin N (2019) Targeting the cell signaling pathway Keap1-Nrf2 as a therapeutic strategy for adenocarcinomas of the lung. Expert Opin Ther Targets 23(3):241–250. https://doi.org/10.1080/14728222.2019.1559824

    Article  CAS  PubMed  Google Scholar 

  30. Walker A, Singh A, Tully E, Woo J, Le A, Nguyen T, Biswal S, Sharma D, Gabrielson E (2018) Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation. Free Radic Biol Med 120:407–413. https://doi.org/10.1016/j.freeradbiomed.2018.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cui Q, Wang JQ, Assaraf YG, Ren L, Gupta P, Wei L, Ashby CR Jr, Yang DH, Chen ZS (2018) Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Updates 41:1–25. https://doi.org/10.1016/j.drup.2018.11.001

    Article  Google Scholar 

  32. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145. https://doi.org/10.1074/jbc.M702824200

    Article  CAS  PubMed  Google Scholar 

  33. Dai X, Yan J, Fu X, Pan Q, Sun D, Xu Y, Wang J, Nie L, Tong L, Shen A, Zheng M, Huang M, Tan M, Liu H, Huang X, Ding J, Geng M (2017) Aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase. Clin Cancer Res 23(20):6267–6278. https://doi.org/10.1158/1078-0432.CCR-17-0242

    Article  CAS  PubMed  Google Scholar 

  34. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, Ahn HJ, Ait-Mohamed O, Ait-Si-Ali S, Akematsu T, Akira S, Al-Younes HM, Al-Zeer MA, Albert ML, Albin RL, Alegre-Abarrategui J, Aleo MF, Alirezaei M, Almasan A, Almonte-Becerril M, Amano A, Amaravadi R, Amarnath S, Amer AO, Andrieu-Abadie N, Anantharam V, Ann DK, Anoopkumar-Dukie S, Aoki H, Apostolova N, Arancia G, Aris JP, Asanuma K, Asare NY, Ashida H, Askanas V, Askew DS, Auberger P, Baba M, Backues SK, Baehrecke EH, Bahr BA, Bai XY, Bailly Y, Baiocchi R, Baldini G, Balduini W, Ballabio A, Bamber BA, Bampton ET, Banhegyi G, Bartholomew CR, Bassham DC, Bast RC Jr, Batoko H, Bay BH, Beau I, Bechet DM, Begley TJ, Behl C, Behrends C, Bekri S, Bellaire B, Bendall LJ, Benetti L, Berliocchi L, Bernardi H, Bernassola F, Besteiro S, Bhatia-Kissova I, Bi X, Biard-Piechaczyk M, Blum JS, Boise LH, Bonaldo P, Boone DL, Bornhauser BC, Bortoluci KR, Bossis I, Bost F, Bourquin JP, Boya P, Boyer-Guittaut M, Bozhkov PV, Brady NR, Brancolini C, Brech A, Brenman JE, Brennand A, Bresnick EH, Brest P, Bridges D, Bristol ML, Brookes PS, Brown EJ, Brumell JH, Brunetti-Pierri N, Brunk UT, Bulman DE, Bultman SJ, Bultynck G, Burbulla LF, Bursch W, Butchar JP, Buzgariu W, Bydlowski SP, Cadwell K, Cahova M, Cai D, Cai J, Cai Q, Calabretta B, Calvo-Garrido J, Camougrand N, Campanella M, Campos-Salinas J, Candi E, Cao L, Caplan AB, Carding SR, Cardoso SM, Carew JS, Carlin CR, Carmignac V, Carneiro LA, Carra S, Caruso RA, Casari G, Casas C, Castino R, Cebollero E, Cecconi F, Celli J, Chaachouay H, Chae HJ, Chai CY, Chan DC, Chan EY, Chang RC, Che CM, Chen CC, Chen GC, Chen GQ, Chen M, Chen Q, Chen SS, Chen W, Chen X, Chen X, Chen X, Chen YG, Chen Y, Chen Y, Chen YJ, Chen Z, Cheng A, Cheng CH, Cheng Y, Cheong H, Cheong JH, Cherry S, Chess-Williams R, Cheung ZH, Chevet E, Chiang HL, Chiarelli R, Chiba T, Chin LS, Chiou SH, Chisari FV, Cho CH, Cho DH, Choi AM, Choi D, Choi KS, Choi ME, Chouaib S, Choubey D, Choubey V, Chu CT, Chuang TH, Chueh SH, Chun T, Chwae YJ, Chye ML, Ciarcia R, Ciriolo MR, Clague MJ, Clark RS, Clarke PG, Clarke R, Codogno P, Coller HA, Colombo MI, Comincini S, Condello M, Condorelli F, Cookson MR, Coombs GH, Coppens I, Corbalan R, Cossart P, Costelli P, Costes S, Coto-Montes A, Couve E, Coxon FP, Cregg JM, Crespo JL, Cronje MJ, Cuervo AM, Cullen JJ, Czaja MJ, D’Amelio M, Darfeuille-Michaud A, Davids LM, Davies FE, De Felici M, de Groot JF, de Haan CA, De Martino L, De Milito A, De Tata V, Debnath J, Degterev A, Dehay B, Delbridge LM, Demarchi F, Deng YZ, Dengjel J, Dent P, Denton D, Deretic V, Desai SD, Devenish RJ, Di Gioacchino M, Di Paolo G, Di Pietro C, Diaz-Araya G, Diaz-Laviada I, Diaz-Meco MT, Diaz-Nido J, Dikic I, Dinesh-Kumar SP, Ding WX, Distelhorst CW, Diwan A, Djavaheri-Mergny M, Dokudovskaya S, Dong Z, Dorsey FC, Dosenko V, Dowling JJ, Doxsey S, Dreux M, Drew ME, Duan Q, Duchosal MA, Duff K, Dugail I, Durbeej M, Duszenko M, Edelstein CL, Edinger AL, Egea G, Eichinger L, Eissa NT, Ekmekcioglu S, El-Deiry WS, Elazar Z, Elgendy M, Ellerby LM, Eng KE, Engelbrecht AM, Engelender S, Erenpreisa J, Escalante R, Esclatine A, Eskelinen EL, Espert L, Espina V, Fan H, Fan J, Fan QW, Fan Z, Fang S, Fang Y, Fanto M, Fanzani A, Farkas T, Farre JC, Faure M, Fechheimer M, Feng CG, Feng J, Feng Q, Feng Y, Fesus L, Feuer R, Figueiredo-Pereira ME, Fimia GM, Fingar DC, Finkbeiner S, Finkel T, Finley KD, Fiorito F, Fisher EA, Fisher PB, Flajolet M, Florez-McClure ML, Florio S, Fon EA, Fornai F, Fortunato F, Fotedar R, Fowler DH, Fox HS, Franco R, Frankel LB, Fransen M, Fuentes JM, Fueyo J, Fujii J, Fujisaki K, Fujita E, Fukuda M, Furukawa RH, Gaestel M, Gailly P, Gajewska M, Galliot B, Galy V, Ganesh S, Ganetzky B, Ganley IG, Gao FB, Gao GF, Gao J, Garcia L, Garcia-Manero G, Garcia-Marcos M, Garmyn M, Gartel AL, Gatti E, Gautel M, Gawriluk TR, Gegg ME, Geng J, Germain M, Gestwicki JE, Gewirtz DA, Ghavami S, Ghosh P, Giammarioli AM, Giatromanolaki AN, Gibson SB, Gilkerson RW, Ginger ML, Ginsberg HN, Golab J, Goligorsky MS, Golstein P, Gomez-Manzano C, Goncu E, Gongora C, Gonzalez CD, Gonzalez R, Gonzalez-Estevez C, Gonzalez-Polo RA, Gonzalez-Rey E, Gorbunov NV, Gorski S, Goruppi S, Gottlieb RA, Gozuacik D, Granato GE, Grant GD, Green KN, Gregorc A, Gros F, Grose C, Grunt TW, Gual P, Guan JL, Guan KL, Guichard SM, Gukovskaya AS, Gukovsky I, Gunst J, Gustafsson AB, Halayko AJ, Hale AN, Halonen SK, Hamasaki M, Han F, Han T, Hancock MK, Hansen M, Harada H, Harada M, Hardt SE, Harper JW, Harris AL, Harris J, Harris SD, Hashimoto M, Haspel JA, Hayashi S, Hazelhurst LA, He C, He YW, Hebert MJ, Heidenreich KA, Helfrich MH, Helgason GV, Henske EP, Herman B, Herman PK, Hetz C, Hilfiker S, Hill JA, Hocking LJ, Hofman P, Hofmann TG, Hohfeld J, Holyoake TL, Hong MH, Hood DA, Hotamisligil GS, Houwerzijl EJ, Hoyer-Hansen M, Hu B, Hu CA, Hu HM, Hua Y, Huang C, Huang J, Huang S, Huang WP, Huber TB, Huh WK, Hung TH, Hupp TR, Hur GM, Hurley JB, Hussain SN, Hussey PJ, Hwang JJ, Hwang S, Ichihara A, Ilkhanizadeh S, Inoki K, Into T, Iovane V, Iovanna JL, Ip NY, Isaka Y, Ishida H, Isidoro C, Isobe K, Iwasaki A, Izquierdo M, Izumi Y, Jaakkola PM, Jaattela M, Jackson GR, Jackson WT, Janji B, Jendrach M, Jeon JH, Jeung EB, Jiang H, Jiang H, Jiang JX, Jiang M, Jiang Q, Jiang X, Jiang X, Jimenez A, Jin M, Jin S, Joe CO, Johansen T, Johnson DE, Johnson GV, Jones NL, Joseph B, Joseph SK, Joubert AM, Juhasz G, Juillerat-Jeanneret L, Jung CH, Jung YK, Kaarniranta K, Kaasik A, Kabuta T, Kadowaki M, Kagedal K, Kamada Y, Kaminskyy VO, Kampinga HH, Kanamori H, Kang C, Kang KB, Kang KI, Kang R, Kang YA, Kanki T, Kanneganti TD, Kanno H, Kanthasamy AG, Kanthasamy A, Karantza V, Kaushal GP, Kaushik S, Kawazoe Y, Ke PY, Kehrl JH, Kelekar A, Kerkhoff C, Kessel DH, Khalil H, Kiel JA, Kiger AA, Kihara A, Kim DR, Kim DH, Kim DH, Kim EK, Kim HR, Kim JS, Kim JH, Kim JC, Kim JK, Kim PK, Kim SW, Kim YS, Kim Y, Kimchi A, Kimmelman AC, King JS, Kinsella TJ, Kirkin V, Kirshenbaum LA, Kitamoto K, Kitazato K, Klein L, Klimecki WT, Klucken J, Knecht E, Ko BC, Koch JC, Koga H, Koh JY, Koh YH, Koike M, Komatsu M, Kominami E, Kong HJ, Kong WJ, Korolchuk VI, Kotake Y, Koukourakis MI, Kouri Flores JB, Kovacs AL, Kraft C, Krainc D, Kramer H, Kretz-Remy C, Krichevsky AM, Kroemer G, Kruger R, Krut O, Ktistakis NT, Kuan CY, Kucharczyk R, Kumar A, Kumar R, Kumar S, Kundu M, Kung HJ, Kurz T, Kwon HJ, La Spada AR, Lafont F, Lamark T, Landry J, Lane JD, Lapaquette P, Laporte JF, Laszlo L, Lavandero S, Lavoie JN, Layfield R, Lazo PA, Le W, Le Cam L, Ledbetter DJ, Lee AJ, Lee BW, Lee GM, Lee J, Lee JH, Lee M, Lee MS, Lee SH, Leeuwenburgh C, Legembre P, Legouis R, Lehmann M, Lei HY, Lei QY, Leib DA, Leiro J, Lemasters JJ, Lemoine A, Lesniak MS, Lev D, Levenson VV, Levine B, Levy E, Li F, Li JL, Li L, Li S, Li W, Li XJ, Li YB, Li YP, Liang C, Liang Q, Liao YF, Liberski PP, Lieberman A, Lim HJ, Lim KL, Lim K, Lin CF, Lin FC, Lin J, Lin JD, Lin K, Lin WW, Lin WC, Lin YL, Linden R, Lingor P, Lippincott-Schwartz J, Lisanti MP, Liton PB, Liu B, Liu CF, Liu K, Liu L, Liu QA, Liu W, Liu YC, Liu Y, Lockshin RA, Lok CN, Lonial S, Loos B, Lopez-Berestein G, Lopez-Otin C, Lossi L, Lotze MT, Low P, Lu B, Lu B, Lu B, Lu Z, Luciano F, Lukacs NW, Lund AH, Lynch-Day MA, Ma Y, Macian F, MacKeigan JP, Macleod KF, Madeo F, Maiuri L, Maiuri MC, Malagoli D, Malicdan MC, Malorni W, Man N, Mandelkow EM, Manon S, Manov I, Mao K, Mao X, Mao Z, Marambaud P, Marazziti D, Marcel YL, Marchbank K, Marchetti P, Marciniak SJ, Marcondes M, Mardi M, Marfe G, Marino G, Markaki M, Marten MR, Martin SJ, Martinand-Mari C, Martinet W, Martinez-Vicente M, Masini M, Matarrese P, Matsuo S, Matteoni R, Mayer A, Mazure NM, McConkey DJ, McConnell MJ, McDermott C, McDonald C, McInerney GM, McKenna SL, McLaughlin B, McLean PJ, McMaster CR, McQuibban GA, Meijer AJ, Meisler MH, Melendez A, Melia TJ, Melino G, Mena MA, Menendez JA, Menna-Barreto RF, Menon MB, Menzies FM, Mercer CA, Merighi A, Merry DE, Meschini S, Meyer CG, Meyer TF, Miao CY, Miao JY, Michels PA, Michiels C, Mijaljica D, Milojkovic A, Minucci S, Miracco C, Miranti CK, Mitroulis I, Miyazawa K, Mizushima N, Mograbi B, Mohseni S, Molero X, Mollereau B, Mollinedo F, Momoi T, Monastyrska I, Monick MM, Monteiro MJ, Moore MN, Mora R, Moreau K, Moreira PI, Moriyasu Y, Moscat J, Mostowy S, Mottram JC, Motyl T, Moussa CE, Muller S, Muller S, Munger K, Munz C, Murphy LO, Murphy ME, Musaro A, Mysorekar I, Nagata E, Nagata K, Nahimana A, Nair U, Nakagawa T, Nakahira K, Nakano H, Nakatogawa H, Nanjundan M, Naqvi NI, Narendra DP, Narita M, Navarro M, Nawrocki ST, Nazarko TY, Nemchenko A, Netea MG, Neufeld TP, Ney PA, Nezis IP, Nguyen HP, Nie D, Nishino I, Nislow C, Nixon RA, Noda T, Noegel AA, Nogalska A, Noguchi S, Notterpek L, Novak I, Nozaki T, Nukina N, Nurnberger T, Nyfeler B, Obara K, Oberley TD, Oddo S, Ogawa M, Ohashi T, Okamoto K, Oleinick NL, Oliver FJ, Olsen LJ, Olsson S, Opota O, Osborne TF, Ostrander GK, Otsu K, Ou JH, Ouimet M, Overholtzer M, Ozpolat B, Paganetti P, Pagnini U, Pallet N, Palmer GE, Palumbo C, Pan T, Panaretakis T, Pandey UB, Papackova Z, Papassideri I, Paris I, Park J, Park OK, Parys JB, Parzych KR, Patschan S, Patterson C, Pattingre S, Pawelek JM, Peng J, Perlmutter DH, Perrotta I, Perry G, Pervaiz S, Peter M, Peters GJ, Petersen M, Petrovski G, Phang JM, Piacentini M, Pierre P, Pierrefite-Carle V, Pierron G, Pinkas-Kramarski R, Piras A, Piri N, Platanias LC, Poggeler S, Poirot M, Poletti A, Pous C, Pozuelo-Rubio M, Praetorius-Ibba M, Prasad A, Prescott M, Priault M, Produit-Zengaffinen N, Progulske-Fox A, Proikas-Cezanne T, Przedborski S, Przyklenk K, Puertollano R, Puyal J, Qian SB, Qin L, Qin ZH, Quaggin SE, Raben N, Rabinowich H, Rabkin SW, Rahman I, Rami A, Ramm G, Randall G, Randow F, Rao VA, Rathmell JC, Ravikumar B, Ray SK, Reed BH, Reed JC, Reggiori F, Regnier-Vigouroux A, Reichert AS, Reiners JJ Jr, Reiter RJ, Ren J, Revuelta JL, Rhodes CJ, Ritis K, Rizzo E, Robbins J, Roberge M, Roca H, Roccheri MC, Rocchi S, Rodemann HP, Rodriguez de Cordoba S, Rohrer B, Roninson IB, Rosen K, Rost-Roszkowska MM, Rouis M, Rouschop KM, Rovetta F, Rubin BP, Rubinsztein DC, Ruckdeschel K, Rucker EB 3rd, Rudich A, Rudolf E, Ruiz-Opazo N, Russo R, Rusten TE, Ryan KM, Ryter SW, Sabatini DM, Sadoshima J, Saha T, Saitoh T, Sakagami H, Sakai Y, Salekdeh GH, Salomoni P, Salvaterra PM, Salvesen G, Salvioli R, Sanchez AM, Sanchez-Alcazar JA, Sanchez-Prieto R, Sandri M, Sankar U, Sansanwal P, Santambrogio L, Saran S, Sarkar S, Sarwal M, Sasakawa C, Sasnauskiene A, Sass M, Sato K, Sato M, Schapira AH, Scharl M, Schatzl HM, Scheper W, Schiaffino S, Schneider C, Schneider ME, Schneider-Stock R, Schoenlein PV, Schorderet DF, Schuller C, Schwartz GK, Scorrano L, Sealy L, Seglen PO, Segura-Aguilar J, Seiliez I, Seleverstov O, Sell C, Seo JB, Separovic D, Setaluri V, Setoguchi T, Settembre C, Shacka JJ, Shanmugam M, Shapiro IM, Shaulian E, Shaw RJ, Shelhamer JH, Shen HM, Shen WC, Sheng ZH, Shi Y, Shibuya K, Shidoji Y, Shieh JJ, Shih CM, Shimada Y, Shimizu S, Shintani T, Shirihai OS, Shore GC, Sibirny AA, Sidhu SB, Sikorska B, Silva-Zacarin EC, Simmons A, Simon AK, Simon HU, Simone C, Simonsen A, Sinclair DA, Singh R, Sinha D, Sinicrope FA, Sirko A, Siu PM, Sivridis E, Skop V, Skulachev VP, Slack RS, Smaili SS, Smith DR, Soengas MS, Soldati T, Song X, Sood AK, Soong TW, Sotgia F, Spector SA, Spies CD, Springer W, Srinivasula SM, Stefanis L, Steffan JS, Stendel R, Stenmark H, Stephanou A, Stern ST, Sternberg C, Stork B, Stralfors P, Subauste CS, Sui X, Sulzer D, Sun J, Sun SY, Sun ZJ, Sung JJ, Suzuki K, Suzuki T, Swanson MS, Swanton C, Sweeney ST, Sy LK, Szabadkai G, Tabas I, Taegtmeyer H, Tafani M, Takacs-Vellai K, Takano Y, Takegawa K, Takemura G, Takeshita F, Talbot NJ, Tan KS, Tanaka K, Tanaka K, Tang D, Tang D, Tanida I, Tannous BA, Tavernarakis N, Taylor GS, Taylor GA, Taylor JP, Terada LS, Terman A, Tettamanti G, Thevissen K, Thompson CB, Thorburn A, Thumm M, Tian F, Tian Y, Tocchini-Valentini G, Tolkovsky AM, Tomino Y, Tonges L, Tooze SA, Tournier C, Tower J, Towns R, Trajkovic V, Travassos LH, Tsai TF, Tschan MP, Tsubata T, Tsung A, Turk B, Turner LS, Tyagi SC, Uchiyama Y, Ueno T, Umekawa M, Umemiya-Shirafuji R, Unni VK, Vaccaro MI, Valente EM, Van den Berghe G, van der Klei IJ, van Doorn W, van Dyk LF, van Egmond M, van Grunsven LA, Vandenabeele P, Vandenberghe WP, Vanhorebeek I, Vaquero EC, Velasco G, Vellai T, Vicencio JM, Vierstra RD, Vila M, Vindis C, Viola G, Viscomi MT, Voitsekhovskaja OV, von Haefen C, Votruba M, Wada K, Wade-Martins R, Walker CL, Walsh CM, Walter J, Wan XB, Wang A, Wang C, Wang D, Wang F, Wang F, Wang G, Wang H, Wang HG, Wang HD, Wang J, Wang K, Wang M, Wang RC, Wang X, Wang X, Wang YJ, Wang Y, Wang Z, Wang ZC, Wang Z, Wansink DG, Ward DM, Watada H, Waters SL, Webster P, Wei L, Weihl CC, Weiss WA, Welford SM, Wen LP, Whitehouse CA, Whitton JL, Whitworth AJ, Wileman T, Wiley JW, Wilkinson S, Willbold D, Williams RL, Williamson PR, Wouters BG, Wu C, Wu DC, Wu WK, Wyttenbach A, Xavier RJ, Xi Z, Xia P, Xiao G, Xie Z, Xie Z, Xu DZ, Xu J, Xu L, Xu X, Yamamoto A, Yamamoto A, Yamashina S, Yamashita M, Yan X, Yanagida M, Yang DS, Yang E, Yang JM, Yang SY, Yang W, Yang WY, Yang Z, Yao MC, Yao TP, Yeganeh B, Yen WL, Yin JJ, Yin XM, Yoo OJ, Yoon G, Yoon SY, Yorimitsu T, Yoshikawa Y, Yoshimori T, Yoshimoto K, You HJ, Youle RJ, Younes A, Yu L, Yu L, Yu SW, Yu WH, Yuan ZM, Yue Z, Yun CH, Yuzaki M, Zabirnyk O, Silva-Zacarin E, Zacks D, Zacksenhaus E, Zaffaroni N, Zakeri Z, Zeh HJ 3rd, Zeitlin SO, Zhang H, Zhang HL, Zhang J, Zhang JP, Zhang L, Zhang L, Zhang MY, Zhang XD, Zhao M, Zhao YF, Zhao Y, Zhao ZJ, Zheng X, Zhivotovsky B, Zhong Q, Zhou CZ, Zhu C, Zhu WG, Zhu XF, Zhu X, Zhu Y, Zoladek T, Zong WX, Zorzano A, Zschocke J, Zuckerbraun B (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8(4):445–544. https://doi.org/10.4161/auto.19496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140(3):313–326. https://doi.org/10.1016/j.cell.2010.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Evans TD, Sergin I, Zhang X, Razani B (2017) Target acquired: selective autophagy in cardiometabolic disease. Sci Signal 10(468):eaag2298. https://doi.org/10.1126/scisignal.aag2298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ichimura Y, Komatsu M (2018) Activation of p62/SQSTM1-Keap1-nuclear factor erythroid 2-related factor 2 pathway in cancer. Front Oncol 8:210. https://doi.org/10.3389/fonc.2018.00210

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chen C, Lu L, Yan S, Yi H, Yao H, Wu D, He G, Tao X, Deng X (2018) Autophagy and doxorubicin resistance in cancer. Anticancer Drugs 29(1):1–9. https://doi.org/10.1097/CAD.0000000000000572

    Article  CAS  PubMed  Google Scholar 

  39. Kumar A, Singh UK, Chaudhary A (2015) Targeting autophagy to overcome drug resistance in cancer therapy. Future Med Chem 7(12):1535–1542. https://doi.org/10.4155/fmc.15.88

    Article  CAS  PubMed  Google Scholar 

  40. Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML, Van Leuven F, Rabano A, Yamamoto M, Rojo AI, Cuadrado A (2016) Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12(10):1902–1916. https://doi.org/10.1080/15548627.2016.1208889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV (2014) Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun 5:3496. https://doi.org/10.1038/ncomms4496

    Article  CAS  PubMed  Google Scholar 

  42. Untereiner AA, Pavlidou A, Druzhyna N, Papapetropoulos A, Hellmich MR, Szabo C (2018) Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells. Biochem Pharmacol 149:174–185. https://doi.org/10.1016/j.bcp.2017.10.007

    Article  CAS  PubMed  Google Scholar 

  43. Nowak-Sliwinska P, Segura T, Iruela-Arispe ML (2014) The chicken chorioallantoic membrane model in biology, medicine and bioengineering. Angiogenesis 17(4):779–804. https://doi.org/10.1007/s10456-014-9440-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ribatti D (2012) Chicken chorioallantoic membrane angiogenesis model. Methods Mol Biol 843:47–57. https://doi.org/10.1007/978-1-61779-523-7_5

    Article  CAS  PubMed  Google Scholar 

  45. Yuan YJ, Xu K, Wu W, Luo Q, Yu JL (2014) Application of the chick embryo chorioallantoic membrane in neurosurgery disease. Int J Med Sci 11(12):1275–1281. https://doi.org/10.7150/ijms.10443

    Article  PubMed  PubMed Central  Google Scholar 

  46. Oliveira C, Granja S, Neves NM, Reis RL, Baltazar F, Silva TH, Martins A (2019) Fucoidan from Fucus vesiculosus inhibits new blood vessel formation and breast tumor growth in vivo. Carbohydr Polym 223:115034. https://doi.org/10.1016/j.carbpol.2019.115034

    Article  CAS  PubMed  Google Scholar 

  47. Dayalan Naidu S, Kostov RV, Dinkova-Kostova AT (2015) Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection. Trends Pharmacol Sci 36(1):6–14. https://doi.org/10.1016/j.tips.2014.10.011

    Article  CAS  PubMed  Google Scholar 

  48. Vomund S, Schafer A, Parnham MJ, Brune B, von Knethen A (2017) Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci 18(12):2772. https://doi.org/10.3390/ijms18122772

    Article  CAS  PubMed Central  Google Scholar 

  49. Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, Karakousi TR, Ellis DC, Bhutkar A, Sanchez-Rivera FJ, Subbaraj L, Martinez B, Bronson RT, Prigge JR, Schmidt EE, Thomas CJ, Goparaju C, Davies A, Dolgalev I, Heguy A, Allaj V, Poirier JT, Moreira AL, Rudin CM, Pass HI, Vander Heiden MG, Jacks T, Papagiannakopoulos T (2017) Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med 23(11):1362–1368. https://doi.org/10.1038/nm.4407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 81502948, 31871407, 31741083, 31870831).

Author information

Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People’s Republic of China

    Na Li, JuYuan Wang, ZhaoYang Wang, Tao Zhang & JunYing Miao

  2. School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People’s Republic of China

    XiaoLing Zang

  3. Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, People’s Republic of China

    BaoXiang Zhao

  4. Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of China

    ZhaoMin Lin

Authors
  1. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JuYuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. XiaoLing Zang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. ZhaoYang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. BaoXiang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. JunYing Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. ZhaoMin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: BZ, JM and ZL. Acquisition of data: NL. Analysis and interpretation of data: NL, ZW and TZ. Writing, review, and/or revision of the manuscript: NL, JW, XZ, ZW and TZ. Study supervision: BZ, JM and ZL. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to BaoXiang Zhao, JunYing Miao or ZhaoMin Lin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All experimental procedures and animal care were approved by the ethics committee of Shandong University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 586 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, N., Wang, J., Zang, X. et al. H2S probe CPC inhibits autophagy and promotes apoptosis by inhibiting glutathionylation of Keap1 at Cys434. Apoptosis 26, 111–131 (2021). https://doi.org/10.1007/s10495-020-01652-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-020-01652-y

Keywords

Search

Navigation