Skip to main content
Log in

UMI-77 primes glioma cells for TRAIL-induced apoptosis by unsequestering Bim and Bak from Mcl-1

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol. UMI-77 alone or in combination with TRAIL untethered pro-apoptotic Bcl-2 proteins Bim and Bak from the sequestration of Mcl-1 and promoted the conformational activation of Bak. Small hairpin RNA (shRNA) of Bid attenuated the cleavage of caspase-8, Bid, caspase-3 and PARP, and reduced the cytotoxicity of UMI-77 plus TRAIL as compared with control shRNA cells, indicating this synergy entails the crosstalk between extrinsic and intrinsic apoptotic signaling. Taken together, UMI-77 enhances TRAIL-induced apoptosis by unsequestering Bim and Bak, which provides a novel therapeutic strategy for the treatment of gliomas.

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

Access this article

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

Abbreviations

TRAIL :

Tumor necrosis factor-related apoptosis-inducing ligand

Mcl-1 :

Myeloid cell leukemia-1

PARP :

Poly-ADP ribose polymerase

shRNA :

Small hairpin RNA

Bcl :

B cell lymphoma

Bid :

BH3-interacting domain death agonist

BH :

Bcl-2 homology

tBid :

Truncated Bid

TNF :

Tumor necrosis factor

FADD :

Fas-associated death domain

DISC :

Death-inducing signaling complex

MOMP :

Mitochondrial outer membrane permeabilization

References

  1. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT (1997) TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. Embo j 16:5386–5397. doi:10.1093/emboj/16.17.5386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113

    Article  CAS  PubMed  Google Scholar 

  3. Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355. doi:10.1038/ni.1714

    Article  CAS  PubMed  Google Scholar 

  4. Gonzalvez F, Ashkenazi A (2010) New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 29:4752–4765. doi:10.1038/onc.2010.221

    Article  CAS  PubMed  Google Scholar 

  5. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163. doi:10.1152/physrev.00013.2006

    Article  CAS  PubMed  Google Scholar 

  6. Lemke J, von Karstedt S, Zinngrebe J, Walczak H (2014) Getting TRAIL back on track for cancer therapy. Cell Death Differ 21:1350–1364. doi:10.1038/cdd.2014.81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamada H, Tada-Oikawa S, Uchida A, Kawanishi S (1999) TRAIL causes cleavage of bid by caspase-8 and loss of mitochondrial membrane potential resulting in apoptosis in BJAB cells. Biochem Biophys Res Commun 265:130–133. doi:10.1006/bbrc.1999.1641

    Article  CAS  PubMed  Google Scholar 

  8. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490

    Article  CAS  PubMed  Google Scholar 

  9. Son JK, Varadarajan S, Bratton SB (2010) TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1. Cell Death Differ 17:1288–1301. doi:10.1038/cdd.2010.9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weber K, Harper N, Schwabe J and Cohen GM (2013) BIM-mediated membrane insertion of the BAK pore domain is an essential requirement for apoptosis. Cell Rep 5:409–420. doi:10.1016/j.celrep.2013.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang S, Sinicrope FA (2008) BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res 68:2944–2951. doi:10.1158/0008-5472.CAN-07-2508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cristofanon S, Fulda S (2012) ABT-737 promotes tBid mitochondrial accumulation to enhance TRAIL-induced apoptosis in glioblastoma cells. Cell Death Dis 3:e432. doi:10.1038/cddis.2012.163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xiao Y, Nimmer P, Sheppard GS, Bruncko M, Hessler P, Lu X, Roberts-Rapp L, Pappano WN, Elmore SW, Souers AJ, Leverson JD, Phillips DC (2015) MCL-1 Is a key determinant of breast cancer cell survival: validation of MCL-1 dependency utilizing a highly selective small molecule inhibitor. Mol Cancer Ther 14:1837–1847. doi:10.1158/1535-7163.MCT-14-0928

    Article  CAS  PubMed  Google Scholar 

  14. Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS, Gulappa T, Cierpicki T, Owens S, Zhang T, Sun D, Stuckey JA, Mohammad RM, Nikolovska-Coleska Z (2014) A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 13:565–575. doi:10.1158/1535-7163.MCT-12-0767

    Article  CAS  PubMed  Google Scholar 

  15. Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W, Jin Z, Liu YY, Dicker DT, Chiao PJ, Flaherty KT, Smith CD, El-Deiry WS (2007) Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 12:66–80. doi:10.1016/j.ccr.2007.05.006

    Article  CAS  PubMed  Google Scholar 

  16. 16.Lemke J, von Karstedt S, Abd El Hay M, Conti A, Arce F, Montinaro A, Papenfuss K, El-Bahrawy MA, Walczak H (2014) Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ 21:491–502. doi:10.1038/cdd.2013.179

    Article  CAS  PubMed  Google Scholar 

  17. Zhu Z, Li K, Xu D, Liu Y, Tang H, Xie Q, Xie L, Liu J, Wang H, Gong Y, Hu Z, Zheng J (2013) ZFX regulates glioma cell proliferation and survival in vitro and in vivo. J Neurooncol 112:17–25. doi:10.1007/s11060-012-1032-z

    Article  CAS  PubMed  Google Scholar 

  18. Zhu Z, Liu Y, Li K, Liu J, Wang H, Sun B, Xiong Z, Jiang H, Zheng J, Hu Z (2014) Protein tyrosine phosphatase receptor U (PTPRU) is required for glioma growth and motility. Carcinogenesis 35:1901–1910. doi:10.1093/carcin/bgu123

    Article  CAS  PubMed  Google Scholar 

  19. van Roosmalen IA, Reis CR, Setroikromo R, Yuvaraj S, Joseph JV, Tepper PG, Kruyt FA and Quax WJ (2014) The ER stress inducer DMC enhances TRAIL-induced apoptosis in glioblastoma. Springerplus 3:495. doi:10.1186/2193-1801-3-495

    Article  PubMed  PubMed Central  Google Scholar 

  20. Eichhorn JM, Alford SE, Sakurikar N, Chambers TC (2014) Molecular analysis of functional redundancy among anti-apoptotic Bcl-2 proteins and its role in cancer cell survival. Exp Cell Res 322:415–424. doi:10.1016/j.yexcr.2014.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee DH, Sung KS, Bartlett DL, Kwon YT, Lee YJ (2015) HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells. Cell Signal 27:293–305. doi:10.1016/j.cellsig.2014.11.013

    Article  CAS  PubMed  Google Scholar 

  22. den Hollander MW, Gietema JA, de Jong S, Walenkamp AM, Reyners AK, Oldenhuis CN, de Vries EG (2013) Translating TRAIL-receptor targeting agents to the clinic. Cancer Lett 332:194–201. doi:10.1016/j.canlet.2012.04.007

    Article  CAS  PubMed  Google Scholar 

  23. Sanchez-Perez T, Ortiz-Ferron G, Lopez-Rivas A (2010) Mitotic arrest and JNK-induced proteasomal degradation of FLIP and Mcl-1 are key events in the sensitization of breast tumor cells to TRAIL by antimicrotubule agents. Cell Death Differ 17:883–894. doi:10.1038/cdd.2009.176

    Article  CAS  PubMed  Google Scholar 

  24. Murphy AC, Weyhenmeyer B, Noonan J, Kilbride SM, Schimansky S, Loh KP, Kogel D, Letai AG, Prehn JH, Murphy BM (2014) Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. Apoptosis 19:629–642. doi:10.1007/s10495-013-0935-2

    Article  CAS  PubMed  Google Scholar 

  25. Wei D, Zhang Q, Schreiber JS, Parsels LA, Abulwerdi FA, Kausar T, Lawrence TS, Sun Y, Nikolovska-Coleska Z, Morgan MA (2015) Targeting mcl-1 for radiosensitization of pancreatic cancers. Transl Oncol 8:47–54. doi:10.1016/j.tranon.2014.12.004

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S, Schuetz JD, Rehg JE, Opferman JT (2013) Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev 27:1351–1364. doi:10.1101/gad.215855.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Perciavalle RM, Opferman JT (2013) Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol 23:22–29. doi:10.1016/j.tcb.2012.08.011

    Article  CAS  PubMed  Google Scholar 

  28. Meng XW, Lee SH, Dai H, Loegering D, Yu C, Flatten K, Schneider P, Dai NT, Kumar SK, Smith BD, Karp JE, Adjei AA, Kaufmann SH (2007) Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. J Biol Chem 282:29831–29846. doi:10.1074/jbc.M706110200

    Article  CAS  PubMed  Google Scholar 

  29. Merino D, Giam M, Hughes PD, Siggs OM, Heger K, O’Reilly LA, Adams JM, Strasser A, Lee EF, Fairlie WD, Bouillet P (2009) The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J Cell Biol 186:355–362. doi:10.1083/jcb.200905153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao L, He F, Liu H, Zhu Y, Tian W, Gao P, He H, Yue W, Lei X, Ni B, Wang X, Jin H, Hao X, Lin J, Chen Q (2012) Natural diterpenoid compound elevates expression of Bim protein, which interacts with antiapoptotic protein Bcl-2, converting it to proapoptotic Bax-like molecule. J Biol Chem 287:1054–1065. doi:10.1074/jbc.M111.264481

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial supports from the Natural Science Foundation of Shanghai (Grant Number 15ZR1409700) are acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Zhi-Chuan Zhu or Jing Zheng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, JW., Zhu, ZC., Li, K. et al. UMI-77 primes glioma cells for TRAIL-induced apoptosis by unsequestering Bim and Bak from Mcl-1. Mol Cell Biochem 432, 55–65 (2017). https://doi.org/10.1007/s11010-017-2997-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-2997-x

Keywords

Navigation