Skip to main content
SpringerLink
Log in

Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins, holds great promise to complement current cancer therapies. However many types of solid cancer cells are resistant to ABT-737. One practical approach to improve its therapeutic efficacy is to combine with the agents that can overcome such resistance to restore the sensitivity. In the present study, a second-generation selenium compound methylseleninic acid (MSeA) synergistically sensitized MDA-MB-231 human breast cancer cells, HT-29 human colon cancer cells and DU145 human prostate cancer cells to apoptosis induction by ABT-737, as evidenced by greater than additive enhancement of Annexin V/FITC positive (apoptotic) cells and activation of multiple caspases and PARP cleavage. Mechanistic investigation demonstrated that MSeA significantly decreased basal Mcl-1 expression and ABT-737-induced Mcl-1 expression. Knocking down of Mcl-1 with RNAi approach supported the functional significance of this molecular target. More importantly, we identified inactivation of Bad by phosphorylation on ser-136 and ser-112 as a novel mechanism involved in ABT-737 resistance, which can be overcome by combining with MSeA. In addition, we found that expression of Bax was required for the efficient execution of synergistic sensitization. Our findings, for the first time, provide a strong mechanistic rationale for developing MSeA as a novel sensitizing agent of ABT-737.

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

Similar content being viewed by others

References

  1. Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17:2941–2953

    PubMed  CAS  Google Scholar 

  2. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Labi V, Grespi F, Baumgartner F, Villunger A (2008) Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death Differ 15:977–987

    Article  PubMed  CAS  Google Scholar 

  5. Oltersdorf T, Elmore SW, Shoemaker AR et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681

    Article  PubMed  CAS  Google Scholar 

  6. van Delft MF, Wei AH, Mason KD et al (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399

    Article  PubMed  Google Scholar 

  7. Konopleva M, Contractor R, Tsao T et al (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388

    Article  PubMed  CAS  Google Scholar 

  8. Vogler M, Dinsdale D, Dyer MJ, Cohen GM (2009) Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 16:360–367

    Article  PubMed  CAS  Google Scholar 

  9. Dai Y, Grant S (2007) Targeting multiple arms of the apoptotic regulatory machinery. Cancer Res 67:2908–2911

    Article  PubMed  CAS  Google Scholar 

  10. Lin X, Morgan-Lappe S, Huang X et al (2007) ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 26:3972–3979

    Article  PubMed  CAS  Google Scholar 

  11. Keuling AM, Felton KE, Parker AA et al (2009) RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One 4:e6651

    Article  PubMed  Google Scholar 

  12. Li H, Stampfer MJ, Giovannucci EL et al (2004) A prospective study of plasma selenium levels and prostate cancer risk. J Natl Cancer Inst 96:696–703

    Article  PubMed  CAS  Google Scholar 

  13. Brooks JD, Metter EJ, Chan DW et al (2001) Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 166:2034–2038

    Article  PubMed  CAS  Google Scholar 

  14. Clark LC, Combs GF Jr, Turnbull BW et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276:1957–1963

    Article  PubMed  CAS  Google Scholar 

  15. Clark LC, Dalkin B, Krongrad A et al (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81:730–734

    Article  PubMed  CAS  Google Scholar 

  16. Yu SY, Zhu YJ, Li WG (1997) Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 56:117–124

    Article  PubMed  CAS  Google Scholar 

  17. Lippman SM, Klein EA, Goodman PJ et al (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301:39–51

    Article  PubMed  CAS  Google Scholar 

  18. Hatfield DL, Gladyshev VN (2009) The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9:18–21

    Article  PubMed  CAS  Google Scholar 

  19. Ledesma MC, Jung-Hynes B, Schmit TL, Kumar R, Mukhtar H, Ahmad N (2011) Selenium and vitamin E for prostate cancer: post-SELECT status. Mol Med 17:134–143

    Article  PubMed  CAS  Google Scholar 

  20. Ip C (1998) Lessons from basic research in selenium and cancer prevention. J Nutr 128:1845–1854

    PubMed  CAS  Google Scholar 

  21. Lu J, Jiang C (2005) Selenium and cancer chemoprevention: hypotheses integrating the actions of selenoproteins and selenium metabolites in epithelial and non-epithelial target cells. Antioxid Redox Signal 7:1715–1727

    Article  PubMed  Google Scholar 

  22. Li GX, Lee HJ, Wang Z et al (2008) Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29:1005–1012

    Article  PubMed  CAS  Google Scholar 

  23. Wang L, Bonorden MJ, Li GX et al (2009) Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2:484–495

    Article  CAS  Google Scholar 

  24. Hu H, Jiang C, Ip C (2005) Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clin Cancer Res 11:2379–2388

    Article  PubMed  CAS  Google Scholar 

  25. Yamaguchi K, Uzzo RG, Pimkina J et al (2005) Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Oncogene 24:5868–5877

    Article  PubMed  CAS  Google Scholar 

  26. Hu H, Li GX, Wang L et al (2008) Methylseleninic acid enhances taxane drug efficacy against human prostate cancer and down-regulates antiapoptotic proteins Bcl-XL and survivin. Clin Cancer Res 14:1150–1158

    Article  PubMed  CAS  Google Scholar 

  27. von Haefen C, Wieder T, Gillissen B et al (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21:4009–4019

    Article  Google Scholar 

  28. Chou T-C, Talalay P (1984) Quantitative analysis of dose effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  29. Bhat UG, Pandit B, Gartel AL (2010) ARC synergizes with ABT-737 to induce apoptosis in human cancer cells. Mol Cancer Ther 9:1688–1696

    Article  PubMed  CAS  Google Scholar 

  30. Morel C, Carlson SM, White FM et al (2009) Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol 29(14):3845–3852

    Article  PubMed  CAS  Google Scholar 

  31. Zha J, Harada H, Yang E et al (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628

    Article  PubMed  CAS  Google Scholar 

  32. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    Article  PubMed  CAS  Google Scholar 

  33. Traini R, Ben-Josef G, Pastrana DV et al (2010) ABT-737 overcomes resistance to immunotoxin-mediated apoptosis and enhances the delivery of pseudomonas exotoxin-based proteins to the cell cytosol. Mol Cancer Ther 9:2007–2015

    Article  PubMed  CAS  Google Scholar 

  34. Huang Y, Hager ER, Phillips DL et al (2003) A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. Clin Cancer Res 9:2769–2777

    PubMed  CAS  Google Scholar 

  35. Okumura K, Huang S, Sinicrope FA (2008) Induction of Noxa sensitizes human colorectal cancer cells expressing Mcl-1 to the small-molecule Bcl-2/Bcl-xL inhibitor, ABT-737. Clin Cancer Res 14:8132–8142

    Article  PubMed  CAS  Google Scholar 

  36. Wang Z, Jiang C, Ganther H, Lü J (2001) Antimitogenic and proapoptotic activities of methylseleninic acid in vascular endothelial cells and associated effects on PI3K-AKT, ERK, JNK and p38 MAPK signaling. Cancer Res 61:7171–7178

    PubMed  CAS  Google Scholar 

  37. Hsieh FC, Cheng G, Lin J (2005) Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 335:292–299

    Article  PubMed  CAS  Google Scholar 

  38. Henderson-Jackson EB, Helm J, Ghayouri M et al (2010) Correlation between Mcl-1 and pAKT protein expression in colorectal cancer. Int J Clin Exp Pathol 3:768–774

    PubMed  Google Scholar 

  39. Krajewska M, Krajewski S, Epstein JI et al (1996) Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol 148:1567–1576

    PubMed  CAS  Google Scholar 

  40. Tahir SK, Yang X, Anderson MG et al (2007) Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res 67:1176–1183

    Article  PubMed  CAS  Google Scholar 

  41. Wesarg E, Hoffarth S, Wiewrodt R et al (2007) Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer 121:2387–2394

    Article  PubMed  CAS  Google Scholar 

  42. Certo M, del Moore GV, Nishino M et al (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365

    Article  PubMed  CAS  Google Scholar 

  43. Datta SR, Ranger AM, Lin MZ et al (2002) Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3:631–643

    Article  PubMed  CAS  Google Scholar 

  44. Kraus AC, Ferber I, Bachmann SO et al (2002) In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 21:8683–8695

    Article  PubMed  CAS  Google Scholar 

  45. Grund K, Ahmadi R, Jung F et al (2008) Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD. Cancer Biol Ther 7:1982–1990

    Article  PubMed  CAS  Google Scholar 

  46. Song JH, Kandasamy K, Zemskova M et al (2011) The BH3 mimetic ABT-737 induces cancer cell senescence. Cancer Res 71(2):506–515

    Article  PubMed  CAS  Google Scholar 

  47. Ara T, Declerck YA (2010) Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 46(7):1223–1231

    Article  PubMed  CAS  Google Scholar 

  48. Reed JC (2006) Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 13:1378–1386

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (NSFC, 30972172, 31071533), Chinese Universities Scientific Fund (2009-2-11), Innovation Fund for Graduate Student of China Agricultural University (Grant KYCX2010064) and the Scientific Research Key Program of Beijing Municipal Commission of Science and Technology (No. 101105046610001).

Conflict of interest

The authors have no conflicts of interest to disclosure.

Author information

Authors and Affiliations

  1. Division of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing, 100083, China

    Shutao Yin, Yinhui Dong, Jinghua Li & Hongbo Hu

  2. College of Veterinary Medicine, China Agricultural University, No. 2 Yunamingyuan West Road, Haidian District, Beijing, 100193, China

    Lihong Fan

  3. The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA

    Lei Wang

  4. Department of Biomedical Sciences, Texas Tech University School of Pharmacy, 1300 S. Coulter, Amarillo, TX, 79106, USA

    Junxuan Lu

  5. Department of Science, Systems and Models, Roskilde University, Bld. 18-1, PO Box 260, 4000, Roskilde, Denmark

    Ole Vang

Authors
  1. Shutao Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinhui Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinghua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lihong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junxuan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ole Vang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongbo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongbo Hu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yin, S., Dong, Y., Li, J. et al. Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad. Apoptosis 17, 388–399 (2012). https://doi.org/10.1007/s10495-011-0687-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-011-0687-9

Keywords

Search

Navigation