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, Seok Hyun Kim, Kazuhiro Ogi, John P. Plastaras, Jianhua Ling, Wenge Wang, Zhaoyu Jin, Yingqiu Y. Liu, David T. Dicker, Paul J. Chiao, Keith T. Flaherty, Charles D. Smith, Wafik S. El-Deiry

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Abstract

Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-κB. Both Myc and the multikinase inhibitor sorafenib block NF-κB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.

Original languageEnglish (US)
Pages (from-to)66-80
Number of pages15
JournalCancer Cell
Volume12
Issue number1
DOIs
StatePublished - Jul 10 2007

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Apoptosis
Neoplasms
Heterografts
Mitochondria
sorafenib
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Ricci, M. Stacey ; Kim, Seok Hyun ; Ogi, Kazuhiro ; Plastaras, John P. ; Ling, Jianhua ; Wang, Wenge ; Jin, Zhaoyu ; Liu, Yingqiu Y. ; Dicker, David T. ; Chiao, Paul J. ; Flaherty, Keith T. ; Smith, Charles D. ; El-Deiry, Wafik S. / Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death. In: Cancer Cell. 2007 ; Vol. 12, No. 1. pp. 66-80.
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abstract = "Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-κB. Both Myc and the multikinase inhibitor sorafenib block NF-κB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.",
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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, vol. 12, no. 1, pp. 66-80. https://doi.org/10.1016/j.ccr.2007.05.006

Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death. / Ricci, M. Stacey; Kim, Seok Hyun; Ogi, Kazuhiro; Plastaras, John P.; Ling, Jianhua; Wang, Wenge; Jin, Zhaoyu; Liu, Yingqiu Y.; Dicker, David T.; Chiao, Paul J.; Flaherty, Keith T.; Smith, Charles D.; El-Deiry, Wafik S.

In: Cancer Cell, Vol. 12, No. 1, 10.07.2007, p. 66-80.

Research output: Contribution to journalArticle

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AU - Ricci, M. Stacey

AU - Kim, Seok Hyun

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AU - Liu, Yingqiu Y.

AU - Dicker, David T.

AU - Chiao, Paul J.

AU - Flaherty, Keith T.

AU - Smith, Charles D.

AU - El-Deiry, Wafik S.

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AB - Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-κB. Both Myc and the multikinase inhibitor sorafenib block NF-κB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.

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