Reduction of TRAIL-induced Mcl-1 and clAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death (Cancer Cell, 2007, 12:66-80)

報告日期: 2007/10/05
報告時間: 16:00/16:50
報告學生: 謝惠娟
講評老師: 王育民
附件下載:

Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to

TRAIL-Induced Death

M. Stacey Ricci, et al. Cancer Cell 12, 66-80 (2007)

 

Speaker: 謝惠娟

Commentator: 王育民 老師

Date: 2007/10/05, 16:10~17:00 pm

Room: room 602

 

Abstract:

 

The conventional cancer therapeutics are often limited by cell toxicities and the selective proliferation of treatment-resistant tumor cells. The death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene. The death receptor ligand Apo2 ligand/tumor necrosis factor alpha-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of TNF superfamily. TRAIL induces apoptosis through its binding to death receptors 4 or 5. TRAIL offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. But not all cells are sensitive to TRAIL. A previous report showed that c-Myc directly represses FLICE-like inhibitory protein (FLIP) expression and determines TRAIL-sensitivity. But, the critical questions are what the underlying mechanisms of TRAIL-resistant are and whether such resistance can be reversed. In this study, the authors found that TRAIL enhanced NF-kB binding to the anti-apoptosis proteins Mcl-1 and cIAP2 promoters and induced their expressions in TRAIL-resistant cells. It was also found that c-Myc repressed TRAIL-induced Mcl-1 and cIAP2 expressions in TRAIL-resistant cells. And TRAIL induced Mcl-1 and cIAP2 expressions through Raf/MEK/ERK pathway in TRAIL-resistant cells. The Raf1 inhibitor sorafenib reduced the ability of NF-kB to bind to the Mcl-1 and cIAP2 promoters and decreased TRAIL-induced Mcl-1 and cIAP2 expressions. Furthermore, the results of in vivo studies in mice showed that treatment with TRAIL and sorafenib also inhibited TRAIL-resistant tumor xenograft growth. In summary, this study demonstrated that combination of TRAIL and sorafenib could be a therapeutic benefit for cancer.

 

Reference:

1.      Mark A. Hall and John L. Cleveland. Clearing the TRAIL for cancer therapy. Cancer cell, 12, 4-6 (2007)

2.      Sean K Kelley and Avi Ashkenazi. Targeting death receptors in cancer with Apo2L/TRAIL. Curr. Opin. Pharmacol., 4, 333-339 (2004)