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FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis

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Abstract

The anthraquinone compound rhein is a natural agent in the traditional Chinese medicine rhubarb. Preclinical studies demonstrate that rhein has anticancer activity. Treatment of a variety of cancer cells with rhein may induce apoptosis. Here, we report that rhein induces atypical unfolded protein response in breast cancer MCF-7 cells and hepatoma HepG2 cells. Rhein induces CHOP expression, eIF2α phosphorylation and caspase cleavage, while it does not induce glucose-regulated protein 78 (GRP78) expression in both MCF-7 and HepG2 cells. Meanwhile, rhein inhibits thapsigargin-induced GRP78 expression and X box-binding protein 1 splicing. In addition, rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity. Rhein induces Bim expression in MCF-7 and HepG2 cells, which can be abrogated by FOXO3a knockdown. Knockdown of FOXO3a or Bim abrogates rhein-induced caspase cleavage and apoptosis. The chemical chaperone 4-phenylbutyrate acid antagonizes the induction of FOXO activation, Bim expression and caspase cleavage by rhein, indicating that protein misfolding may be involved in triggering these deleterious effects. We conclude that FOXO3a-mediated up-regulation of Bim is a key mechanism underlying rhein-induced cancer cells apoptosis.

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References

  1. Ip SW, Weng YS, Lin SY, Mei-Dueyang, Tang NY, Su CC et al (2007) The role of Ca2+ on rhein-induced apoptosis in human cervical cancer Ca Ski cells. Anticancer Res 27:379–389

    CAS  PubMed  Google Scholar 

  2. Lin ML, Chen SS, Lu YC, Liang RY, Ho YT, Yang CY et al (2007) Rhein induces apoptosis through induction of endoplasmic reticulum stress and Ca2+-dependentmitochondrial death pathway in human nasopharyngeal carcinoma cells. Anticancer Res 27:3313–3322

    CAS  PubMed  Google Scholar 

  3. Chang CY, Chan HL, Lin HY, Way TD, Kao MC, Song MZ et al (2012) Rhein induces apoptosis in human breast cancer cells. Evid Based Complement Altern Med 2012:952504

    Google Scholar 

  4. Lai WW, Yang JS, Lai KC, Kuo CL, Hsu CK, Wang CK et al (2009) Rhein induced apoptosis through the endoplasmic reticulum stress, caspase- and mitochondria-dependent pathways in SCC-4 human tongue squamous cancer cells. In Vivo 23:309–316

    CAS  PubMed  Google Scholar 

  5. Miccadei S, Pulselli R, Floridi A (1993) Effect of lonidamine and rhein on the phosphorylation potential generated by respiring rat liver mitochondria. Anticancer Res 13:1507–1510

    CAS  PubMed  Google Scholar 

  6. Lin YJ, Zhen YS (2009) Rhein lysinate suppresses the growth of breast cancer cells and potentiates the inhibitory effect of Taxol in athymic mice. Anticancer Drugs 20:65–72

    Article  CAS  PubMed  Google Scholar 

  7. Lin YJ, Zhen YZ, Shang BY, Zhen YS (2009) Rhein lysinate suppresses the growth of tumor cells and increases the anti-tumor activity of Taxol in mice. Am J Chin Med 37:923–931

    Article  CAS  PubMed  Google Scholar 

  8. Raimondi F, Santoro P, Maiuri L, Londei M, Annunziata S, Ciccimarra F et al (2002) Reactive nitrogen species modulate the effects of rhein, an active component of senna laxatives, on human epithelium in vitro. J Pediatr Gastroenterol Nutr 34:529–534

    Article  PubMed  Google Scholar 

  9. Hsia TC, Yang JS, Chen GW, Chiu TH, Lu HF, Yang MD et al (2009) The roles of endoplasmic reticulum stress and Ca2+ on rhein-induced apoptosis in A-549 human lung cancer cells. Anticancer Res 29:309–318

    CAS  PubMed  Google Scholar 

  10. Pattacini L, Mancini M, Mazzacurati L, Brusa G, Benvenuti M, Martinelli G et al (2004) Endoplasmic reticulum stress initiates apoptotic death induced by STI571 inhibition of p210 bcr-abl tyrosine kinase. Leuk Res 28:191–202

    Article  CAS  PubMed  Google Scholar 

  11. Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS (2007) The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 67:9809–9816

    Article  CAS  PubMed  Google Scholar 

  12. Luo B, Lee AS (2013) The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32:805–818

    Article  CAS  PubMed  Google Scholar 

  13. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349

    Article  CAS  PubMed  Google Scholar 

  15. Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA et al (2003) FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278:49795–49805

    Article  CAS  PubMed  Google Scholar 

  16. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC et al (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss isovercome by a BH3 mimetic. Proc Natl Acad Sci USA 103:14907–14912

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG et al (2008) Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 22:808–818

    Article  CAS  PubMed  Google Scholar 

  18. Jiang CC, Chen LH, Gillespie S, Wang YF, Kiejda KA, Zhang XD et al (2007) Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res 67:9750–9761

    Article  CAS  PubMed  Google Scholar 

  19. Zhang LJ, Chen S, Wu P, Hu CS, Thorne RF, Luo CM et al (2009) Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells. Cancer Lett 274:40–46

    Article  CAS  PubMed  Google Scholar 

  20. Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380

    Article  CAS  PubMed  Google Scholar 

  21. Pigneux A, Mahon FX, Moreau-Gaudry F, Uhalde M, de Verneuil H, Lacombe F et al (2007) Proteasome inhibition specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins. Cancer Biol Ther 6:603–611

    Article  CAS  PubMed  Google Scholar 

  22. Tanizaki J, Okamoto I, Fumita S, Okamoto W, Nishio K, Nakagawa K (2011) Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification. Oncogene 30:4097–4106

    Article  CAS  PubMed  Google Scholar 

  23. Wilk A, Urbanska K, Grabacka M, Mullinax J, Marcinkiewicz C, Impastato D et al (2012) Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro. Cell Cycle 11:2660–2671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC et al (2004) The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J Biol Chem 279:1513–1525

    Article  CAS  PubMed  Google Scholar 

  25. Santo EE, Stroeken P, Sluis PV, Koster J, Versteeg R, Westerhout EM (2013) FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma. Cancer Res 73:2189–2198

    Article  CAS  PubMed  Google Scholar 

  26. de Almeida SF, Picarote G, Fleming JV, Carmo-Fonseca M, Azevedo JE, de Sousa M (2007) Chemical chaperones reduce endoplasmic reticulum stress and prevent mutant HFE aggregate formation. J Biol Chem 282:27905–27912

    Article  PubMed  Google Scholar 

  27. Zode GS, Kuehn MH, Nishimura DY, Searby CC, Mohan K, Grozdanic SD et al (2011) Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of Primary open angle glaucoma. J Clin Invest. 121:3542–3553

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Brookes SJ, Barron MJ, Boot-Handford R, Kirkham J, Dixon MJ (2014) Endoplasmic reticulum stress in amelogenesis imperfecta and phenotypic rescue using 4-phenylbutyrate. Hum Mol Genet 23:2468–2480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Kuo PL, Hsu YL, Ng LT, Lin CC (2004) Rhein inhibits the growth and induces the apoptosis of HepG2 cells. Planta Med 70:12–16

    Article  CAS  PubMed  Google Scholar 

  30. Lin S, Fujii M, Hou DX (2003) Rhein induces apoptosis in HL-60 cells via reactive oxygen species-independent mitochondrial death pathway. Arch Biochem Biophys 418:99–107

    Article  CAS  PubMed  Google Scholar 

  31. Floridi A, Castiglione S, Bianchi C, Mancini A (1990) Effect of rhein on the glucose metabolism of Ehrlich ascites tumor cells. Biochem Pharmacol 40:217–222

    Article  CAS  PubMed  Google Scholar 

  32. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102

    CAS  PubMed  Google Scholar 

  33. Zhang LH, Zhang X (2010) Roles of GRP78 in physiology and cancer. J Cell Biochem 110:1299–1305

    Article  CAS  PubMed  Google Scholar 

  34. Beck D, Niessner H, Smalley KS, Flaherty K, Paraiso KH, Busch C et al (2013) Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. Sci Signal 6: ra7

  35. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B et al (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45:487–498

    Article  CAS  PubMed  Google Scholar 

  36. Rolland SG, Conradt B (2010) New role of the BCL2 family of proteins in the regulation of mitochondrial dynamics. Curr Opin Cell Biol 22:852–858

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Akiyama T, Dass CR, Choong PF (2009) Bim-targeted cancer therapy: a link between drug action and underlying molecular changes. Mol Cancer Ther 8:3173–3180

    Article  CAS  PubMed  Google Scholar 

  39. Ghosh AP, Klocke BJ, Ballestas ME, Roth KA (2012) CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress. PLoS One 7:e39586

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Lin Y, Wang Z, Liu L, Chen L (2011) Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells. Lung Cancer 71:291–297

    Article  PubMed  Google Scholar 

  41. Fu Y, Wey S, Wang M, Ye R, Liao CP, Roy-Burman P et al (2008) Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci 105:19444–19449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Peng Y, Sun JG, Wang GJ (2009) Pharmacokinetic study of rhein and its carboxyl-esterification derivatives in rats. Chin J Nat Med 7:228–233

    Article  CAS  Google Scholar 

  43. Jiang JY, Yang MW, Qian W, Lin H, Geng Y, Zhou ZQ et al (2011) Quantitative determination of rhein in human plasma by liquid chromatography-negative electrospray ionization tandem mass/mass spectrometry and the application in a pharmacokinetic study. J Pharm Biomed Anal 57:19–25

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank for the support from National Natural Science Foundation of China (No. 81001587).

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China

    Jiao Wang

  2. State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, China

    Shu Liu, Yancun Yin, Bo Wang, Li Yang & Yangfu Jiang

  3. Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China

    Mingjin Li

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  1. Jiao Wang
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Correspondence to Yangfu Jiang.

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Wang, J., Liu, S., Yin, Y. et al. FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis. Apoptosis 20, 399–409 (2015). https://doi.org/10.1007/s10495-014-1071-3

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  • DOI: https://doi.org/10.1007/s10495-014-1071-3

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