TY - JOUR
T1 - Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation
AU - Zhu, Hongbo
AU - Guo, Wei
AU - Zhang, Lidong
AU - Wu, Shuhong
AU - Teraishi, Fuminori
AU - Davis, John J.
AU - Dong, Fengqin
AU - Fang, Bingliang
N1 - Funding Information:
However, the underlying mechanisms of the resensitization of TRAIL-induced apoptosis by some proteasome inhibitors, such as calpain inhibitor I, remain unclear.7 Moreover, This work was supported in part by National several recent studies have demonstrated that proteasome inhibitors can overcome resistance Cancer Institute grants CA 092487-01A1 and CA to TRAIL in cancer cells of blood, colon, prostate, and bladder origin by different Lockton Grant Matching Fund. This article repre-098582-01A1 (to B.F.), and CA16672 and by mechanisms, including upregulation of death receptor (DR4) and DR5, downregulation sents partial fulfillment of the requirements for a of Flice inhibitory protein (FLIP), and inhibition of NFκB activation.8-11
PY - 2005/7
Y1 - 2005/7
N2 - Proteasome inhibitors can resensitize cells that are resistant to tumor 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, Bel-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 resensitization of TRAIL.
AB - Proteasome inhibitors can resensitize cells that are resistant to tumor 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, Bel-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 resensitization of TRAIL.
KW - Bik
KW - Bortezomib
KW - Death receptor 5
KW - PS-341
KW - Proteasome inhibitor
KW - Resistance
KW - Tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)
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U2 - 10.4161/cbt.4.7.1897
DO - 10.4161/cbt.4.7.1897
M3 - Article
C2 - 16082182
AN - SCOPUS:25144521280
VL - 4
SP - 781
EP - 786
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 7
ER -