Proteasome Inhibitors-Mediated TRAIL Resensitization and Bik Accumulation

Hongbo Zhu

Wei Guo

Lidong Zhang

Shuhong Wu

^{Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, China}

^{Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA}

^{Program in Gene Therapy and Virology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA\}

*Corresponding author: B. Fang, Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Phone: (713) 563-9147. Fax: (713) 794-4669. E-mail: gro.nosrednadm@gnafb.

Abstract

Proteasome inhibitors can resensitize cells that are resistant to tumors necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly (ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL, or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated re-sensitization of TRAIL.

Keywords: Proteasome inhibitor, bortezomib, PS-341, tumor necrosis factor-related apoptotic-inducing ligand (TRAIL), resistance, death receptor 5, Bik

Abstract

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