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Experimental and Molecular Therapeutics

Abstract 2981: DNA damaging agent-induced apoptosis is controled by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex

Wataru Nakajima, June Y. Lee, Nicolas Maxim, Kanika Sharma, Mark A. Hicks, Thien-Trang Vu, Angela Luu, William Andrew Yeudall, Nobuyuki Tanaka and Hisashi Harada
Wataru Nakajima
VCU Massey Cancer Center, Richmond, VA;
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June Y. Lee
VCU Massey Cancer Center, Richmond, VA;
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Nicolas Maxim
VCU Massey Cancer Center, Richmond, VA;
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Kanika Sharma
VCU Massey Cancer Center, Richmond, VA;
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Mark A. Hicks
VCU Massey Cancer Center, Richmond, VA;
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Thien-Trang Vu
VCU Massey Cancer Center, Richmond, VA;
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Angela Luu
VCU Massey Cancer Center, Richmond, VA;
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William Andrew Yeudall
Georgia Regents University, Augusta, GA;
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Nobuyuki Tanaka
Nippon Medical School, Kawasaki, Japan.
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Hisashi Harada
VCU Massey Cancer Center, Richmond, VA;
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DOI: 10.1158/1538-7445.AM2016-2981 Published July 2016
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Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

Abstract

DNA damaging agents, such as cisplatin and etoposide, are employed for the treatment of a wide array of solid tumors, but the prolonged use of chemotherapeutic drugs is limited by their toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies that maximize the antitumor effect of drugs while limiting their toxicities. These agents exert anticancer effects via multiple mechanisms, yet their most prominent mode of action involves the generation of DNA lesions followed by activation of the DNA damage response and induction of the BCL-2 family-dependent mitochondrial apoptosis. However, the signaling pathways that connect to BCL-2-family-regulated cell death are not entirely clear.

Noxa, a BH3-only pro-apoptotic BCL-2 family protein, causes apoptosis by specifically interacting with the anti-apoptotic BCL-2 family protein MCL-1 to induce its proteasome-mediated degradation. We show here that the DNA damaging agents cisplatin and etoposide upregulate Noxa expression, which is required for the phosphorylation of MCL-1 at Ser64/Thr70 sites, proteasome-dependent degradation, and as a consequence, apoptosis. Noxa-induced MCL-1 phosphorylation at these sites occurs at the mitochondria and is primarily regulated by CDK2. MCL-1 and CDK2 form a stable complex and Noxa binds to this complex to facilitate the phosphorylation of MCL-1. When Ser64 and Thr70 of MCL-1 are substituted with alanine, the mutated MCL-1 is neither phosphorylated nor ubiquitinated, and becomes more stable than the wild-type protein. As a consequence, this mutant can inhibit apoptosis induced by Noxa overexpression or cisplatin treatment. These results indicate that Noxa-mediated MCL-1 phosphorylation followed by MCL-1 degradation is critical for apoptosis induced by DNA damaging agents through regulation of the Noxa/MCL-1/CDK2 complex. Of note, the identified phosphorylation sites are only observed in human MCL-1; thus, the regulatory mechanism shown here may be human-specific. It is of interest in the future to analyze whether CDK2 expression/activity correlates to cisplatin-resistance in patient samples.

Citation Format: Wataru Nakajima, June Y. Lee, Nicolas Maxim, Kanika Sharma, Mark A. Hicks, Thien-Trang Vu, Angela Luu, William Andrew Yeudall, Nobuyuki Tanaka, Hisashi Harada. DNA damaging agent-induced apoptosis is controled by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2981.

  • ©2016 American Association for Cancer Research.
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Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
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Abstract 2981: DNA damaging agent-induced apoptosis is controled by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex
Wataru Nakajima, June Y. Lee, Nicolas Maxim, Kanika Sharma, Mark A. Hicks, Thien-Trang Vu, Angela Luu, William Andrew Yeudall, Nobuyuki Tanaka and Hisashi Harada
Cancer Res July 15 2016 (76) (14 Supplement) 2981; DOI: 10.1158/1538-7445.AM2016-2981

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Abstract 2981: DNA damaging agent-induced apoptosis is controled by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex
Wataru Nakajima, June Y. Lee, Nicolas Maxim, Kanika Sharma, Mark A. Hicks, Thien-Trang Vu, Angela Luu, William Andrew Yeudall, Nobuyuki Tanaka and Hisashi Harada
Cancer Res July 15 2016 (76) (14 Supplement) 2981; DOI: 10.1158/1538-7445.AM2016-2981
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