Abstract
Resolution to chemoresistance is a major challenge in patients with advanced-stage malignancies. Thus, identification of action points and elucidation of molecular mechanisms for chemoresist human cancer are necessary to overcome this challenge. In this study, we provide important evidence that kaempferol targeting RSKs might be a strategy to reduce the oxaliplatin-resistant colon cancer cells. We found that MAPK and PI3K-AKT signaling were increased in oxaliplatin (Ox)-resistant HCT116 (HCT116-OxR) cells compared to Ox-sensitive HCT116 (HCT116-OxS) cells. Comparison of cell sensitivities using SP600125 (JNK inhibitor), SB206580 (p38 kinase inhibitor), or MK-2206 (AKT inhibitor) revealed that cell proliferation inhibition was strongly observed in HT29 cells compared to that in HCT116 cells in both OxS and OxR cells. Interestingly, SP600125, SB206580, and MK-2206 treatment showed higher cell proliferation inhibition in OxS cells than that in OxR cells in both HCT116 and HT29 cells, except following treatments with 10 µM of SP600125, and 30 µM of SB206580. In comparison to magnolin and aschantin, kaempferol showed the strongest inhibitory effect on cell proliferation in both HCT116 and HT29 cells. Importantly, HCT116- and HT29-OxR cells showed higher sensitivities to cell proliferation inhibition than those of HCT116- and HT29-OxS cells, resulting in the accumulation of cells at the G2/M-phases of the cell cycle. Finally, we showed that AP-1 transactivation activity was markedly decreased by kaempferol in HCT116- and HT29-OxR cells compared to the activity levels in HCT116- and HT29-OxS cells. Taken together, the results demonstrate that kaempferol-mediated AP-1 inhibition might be an important signaling mechanism to resolve the chemoresistance of Ox-resistant colon cancer cells.
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References
Aksamitiene E, Kiyatkin A, Kholodenko BN (2012) Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans 40:139–146. https://doi.org/10.1042/BST20110609
Barlow AD, Xie J, Moore CE, Campbell SC, Shaw JA, Nicholson ML, Herbert TP (2012) Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia 55:1355–1365. https://doi.org/10.1007/s00125-012-2475-7
Bose D, Zimmerman LJ, Pierobon M, Petricoin E, Tozzi F, Parikh A, Fan F, Dallas N, Xia L, Gaur P, Samuel S, Liebler DC, Ellis LM (2011) Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells. Br J Cancer 105:1759–1767. https://doi.org/10.1038/bjc.2011.449
Bradbury CM, Locke JE, Wei SJ, Rene LM, Karimpour S, Hunt C, Spitz DR, Gius D (2001) Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells. Cancer Res 61:3486–3492 (PMID: 11309312)
Cao P, Xia Y, He W, Zhang T, Hong L, Zheng P, Shen X, Liang G, Cui R, Zou P (2019) Enhancement of oxaliplatin-induced colon cancer cell apoptosis by alantolactone, a natural product inducer of ROS. Int J Biol Sci 15:1676–1684. https://doi.org/10.7150/ijbs.35265
Chae SH, Kim PS, Cho JY, Park JS, Lee JH, Yoo ES, Baik KU, Lee JS, Park MH (1998) Isolation and identification of inhibitory compounds on TNF-alpha production from Magnolia fargesii. Arch Pharm Res 21:67–69. https://doi.org/10.1007/BF03216755
Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Basecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Laidler P, Milella M, Tafuri A, Bonati A, Evangelisti C, Cocco L, Martelli AM, Mccubrey JA (2011) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2:135–164. https://doi.org/10.18632/oncotarget.240
Chen AY, Chen YC (2013) A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem 138:2099–2107. https://doi.org/10.1016/j.foodchem.2012.11.139
Cho YY (2017a) Molecular Targeting of ERKs/RSK2 Signaling in Cancers. Curr Pharm Des 23:4247–4258. https://doi.org/10.2174/1381612823666170714142338
Cho YY (2017b) RSK2 and its binding partners in cell proliferation, transformation and cancer development. Arch Pharm Res 40:291–303. https://doi.org/10.1007/s12272-016-0880-z
Cho YY, Lee MH, Lee CJ, Yao K, Lee HS, Bode AM, Dong Z (2012) RSK2 as a key regulator in human skin cancer. Carcinogenesis 33:2529–2537. https://doi.org/10.1093/carcin/bgs271
Cho YY, Yao K, Kim HG, Kang BS, Zheng D, Bode AM, Dong Z (2007) Ribosomal S6 kinase 2 is a key regulator in tumor promoter induced cell transformation. Cancer Res 67:8104–8112. https://doi.org/10.1158/0008-5472.CAN-06-4668
Cho YY, Yao K, Pugliese A, Malakhova ML, Bode AM, Dong Z (2009) A regulatory mechanism for RSK2 NH(2)-terminal kinase activity. Cancer Res 69:4398–4406. https://doi.org/10.1158/0008-5472.CAN-08-4959
Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 70:288–298. https://doi.org/10.1158/0008-5472.CAN-09-1751
Colburn NH, Wendel EJ, Abruzzo G (1981) Dissociation of mitogenesis and late-stage promotion of tumor cell phenotype by phorbol esters: mitogen-resistant variants are sensitive to promotion. Proc Natl Acad Sci U S A 78:6912–6916
Cree IA (2009) Chemosensitivity and chemoresistance testing in ovarian cancer. Curr Opin Obstet Gynecol 21:39–43. https://doi.org/10.1097/GCO.0b013e32832210ff
Cullen PJ, Lockyer PJ (2002) Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol 3:339–348. https://doi.org/10.1038/nrm808
Dupont MS, Day AJ, Bennett RN, Mellon FA, Kroon PA (2004) Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans. Eur J Clin Nutr 58:947–954. https://doi.org/10.1038/sj.ejcn.1601916
Goel G (2018) Molecular characterization and biomarker identification in colorectal cancer: toward realization of the precision medicine dream. Cancer Manag Res 10:5895–5908. https://doi.org/10.2147/CMAR.S162967
Holt SV, Logie A, Davies BR, Alferez D, Runswick S, Fenton S, Chresta CM, Gu Y, Zhang J, Wu YL, Wilkinson RW, Guichard SM, Smith PD (2012) Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res 72:1804–1813. https://doi.org/10.1158/0008-5472.CAN-11-1780
Jeong HU, Lee JY, Kwon SS, Kim JH, Kim YM, Hong SW, Yeon SH, Lee SM, Cho YY, Lee HS (2015) Metabolism-mediated drug interaction potential of HS-23, a new herbal drug for the treatment of sepsis in human hepatocytes and liver microsomes. Arch Pharm Res 38:171–177. https://doi.org/10.1007/s12272-014-0453-y
Koveitypour Z, Panahi F, Vakilian M, Peymani M, Seyed Forootan F, Nasr Esfahani MH, Ghaedi K (2019) Signaling pathways involved in colorectal cancer progression. Cell Biosci 9:97. https://doi.org/10.1186/s13578-019-0361-4
Lee CJ, Jang JH, Lee JY, Lee MH, Li Y, Ryu HW, Choi KI, Dong Z, Lee HS, Oh SR, Surh YJ, Cho YY (2015) Aschantin targeting on the kinase domain of mammalian target of rapamycin suppresses epidermal growth factor-induced neoplastic cell transformation. Carcinogenesis 36:1223–1234. https://doi.org/10.1093/carcin/bgv113
Lee CJ, Lee HS, Ryu HW, Lee MH, Lee JY, Li Y, Dong Z, Lee HK, Oh SR, Cho YY (2014) Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation. Carcinogenesis 35:432–441. https://doi.org/10.1093/carcin/bgt306
Lee CJ, Lee MH, Lee JY, Song JH, Lee HS, Cho YY (2013) RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3beta activity. Biochem Biophys Res Commun 440:112–118. https://doi.org/10.1016/j.bbrc.2013.09.042
Lee CJ, Moon SJ, Jeong JH, Lee S, Lee MH, Yoo SM, Lee HS, Kang HC, Lee JY, Lee WS, Lee HJ, Kim EK, Jhun JY, Cho ML, Min JK, Cho YY (2018) Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis. Cell Death Dis 9:401. https://doi.org/10.1038/s41419-018-0433-0
Lee DW, Han SW, Cha Y, Bae JM, Kim HP, Lyu J, Han H, Kim H, Jang H, Bang D, Huh I, Park T, Won JK, Jeong SY, Park KJ, Kang GH, Kim TY (2017) Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer. Cancer 123:3513–3523. https://doi.org/10.1002/cncr.30760
Li N, Zhang Z, Jiang G, Sun H, Yu D (2019) Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway. Front Biosci (landmark Ed) 24:303–312. https://doi.org/10.2741/4719
Lim HC, Xie L, Zhang W, Li R, Chen ZC, Wu GZ, Cui SS, Tan EK, Zeng L (2013) Ribosomal S6 Kinase 2 (RSK2) maintains genomic stability by activating the Atm/p53-dependent DNA damage pathway. PLoS ONE 8:e74334. https://doi.org/10.1371/journal.pone.0074334
Liu ZG, Jiang G, Tang J, Wang H, Feng G, Chen F, Tu Z, Liu G, Zhao Y, Peng MJ, He ZW, Chen XY, Lindsay H, Xia YF, Li XN (2016) c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma. Oncotarget 7:65946–65956. https://doi.org/10.18632/oncotarget.11779
Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205:275–292
Min HY, Lee HY (2021) Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch Pharm Res 44:146–164. https://doi.org/10.1007/s12272-021-01312-y
Papadatos-Pastos D, Rabbie R, Ross P, Sarker D (2015) The role of the PI3K pathway in colorectal cancer. Crit Rev Oncol Hematol 94:18–30. https://doi.org/10.1016/j.critrevonc.2014.12.006
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183. https://doi.org/10.1210/edrv.22.2.0428
Peng C, Cho YY, Zhu F, Zhang J, Wen W, Xu Y, Yao K, Ma WY, Bode AM, Dong Z (2011) Phosphorylation of caspase-8 (Thr-263) by ribosomal S6 kinase 2 (RSK2) mediates caspase-8 ubiquitination and stability. J Biol Chem 286:6946–6954. https://doi.org/10.1074/jbc.M110.172338
Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, Arnold A (1999) The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev 20:501–534. https://doi.org/10.1210/edrv.20.4.0373
Poulikakos PI, Solit DB (2011) Resistance to MEK inhibitors: should we co-target upstream? Sci Signal 4:pe16. https://doi.org/10.1126/scisignal.2001948
Prior IA, Hood FE, Hartley JL (2020) The Frequency of Ras Mutations in Cancer. Cancer Res 80:2969–2974. https://doi.org/10.1158/0008-5472.CAN-19-3682
Roymans D, Slegers H (2001) Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 268:487–498
Rubinfeld H, Seger R (2005) The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol 31:151–174. https://doi.org/10.1385/MB:31:2:151
Seok JK, Kang HC, Cho YY, Lee HS, Lee JY (2021) Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch Pharm Res 44:16–35. https://doi.org/10.1007/s12272-021-01307-9
Song JH, Lee CJ, An HJ, Yoo SM, Kang HC, Lee JY, Kim KD, Kim DJ, Lee HS, Cho YY (2019) Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells. Mol Carcinog 58:88–101. https://doi.org/10.1002/mc.22909
Sulzmaier FJ, Young-Robbins S, Jiang P, Geerts D, Prechtl AM, Matter ML, Kesari S, Ramos JW (2016) RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics. Oncotarget 7:79869–79884. https://doi.org/10.18632/oncotarget.13084
Sun W, Ge Y, Cui J, Yu Y, Liu B (2021) Scutellarin resensitizes oxaliplatin-resistant colorectal cancer cells to oxaliplatin treatment through inhibition of PKM2. Mol Ther Oncolytics 21:87–97. https://doi.org/10.1016/j.omto.2021.03.010
Temraz S, Mukherji D, Shamseddine A (2015) Dual inhibition of MEK and PI3K pathway in KRAS and BRAF mutated colorectal cancers. Int J Mol Sci 16:22976–22988. https://doi.org/10.3390/ijms160922976
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501. https://doi.org/10.1038/nrc839
Wan YW, Sabbagh E, Raese R, Qian Y, Luo D, Denvir J, Vallyathan V, Castranova V, Guo NL (2010) Hybrid models identified a 12-gene signature for lung cancer prognosis and chemoresponse prediction. PLoS ONE 5:e12222. https://doi.org/10.1371/journal.pone.0012222
Wang Q, Shi YL, Zhou K, Wang LL, Yan ZX, Liu YL, Xu LL, Zhao SW, Chu HL, Shi TT, Ma QH, Bi J (2018a) PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis 9:739. https://doi.org/10.1038/s41419-018-0776-6
Wang Y, Wan GH, Wu YM, Wang HS, Wang HF, Zhang G, Lu LL, Li ZQ, Chan KY, Zhou Y, Cai SH, Qi YF, Du J (2018b) AP-1 confers resistance to anti-cancer therapy by activating XIAP. Oncotarget 9:14124–14137. https://doi.org/10.18632/oncotarget.23897
Wei Y, Yang P, Cao S, Zhao L (2018) The combination of curcumin and 5-fluorouracil in cancer therapy. Arch Pharm Res 41:1–13. https://doi.org/10.1007/s12272-017-0979-x
Wilson TR, Longley DB, Johnston PG (2006) Chemoresistance in solid tumours. Ann Oncol 17(Suppl 10):x315–x324. https://doi.org/10.1093/annonc/mdl280
Yoo SM, Lee CJ, An HJ, Lee JY, Lee HS, Kang HC, Cho SJ, Kim SM, Park J, Kim DJ, Cho YY (2019a) RSK2-mediated ELK3 activation enhances cell transformation and breast cancer cell growth by regulation of c-fos promoter activity. Int J Mol Sci. https://doi.org/10.3390/ijms20081994
Yoo SM, Lee CJ, Kang HC, Lee HS, Lee JY, Kim KD, Kim DJ, An HJ, Cho YY (2019b) Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells. Mol Carcinog 58:1221–1233. https://doi.org/10.1002/mc.23005
Acknowledgements
Ox-sensitive parent cells, HT29-OxS and HCT116-OxS, and Ox-resistant HT29-OxR and HCT116-OxR cells, were a generous gift from Dr. L.M., Ellis, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. This research was funded by the Research Fund of The Catholic University of Korea (M‐2021‐B0002‐00029), the Ministry of Science, ICT and Future Planning (NRF‐2020R1A2B5B02001804 and NRF‐2020R1A4A2002894), and the Ministry of Education (BK21 Four‐sponsored Advanced Program for SmartPharma Leaders 4299990814607).
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Park, J., Lee, GE., An, HJ. et al. Kaempferol sensitizes cell proliferation inhibition in oxaliplatin-resistant colon cancer cells. Arch. Pharm. Res. 44, 1091–1108 (2021). https://doi.org/10.1007/s12272-021-01358-y
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DOI: https://doi.org/10.1007/s12272-021-01358-y