2. Academic Validation
  3. Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy

Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy

  • Cancer Lett. 2018 Oct 28;435:44-54. doi: 10.1016/j.canlet.2018.07.033.
Guoqing Qian 1,  Weilong Yao 2,  Shuo Zhang 3,  Richa Bajpai 1,  William D Hall 1,  Mala Shanmugam 1,  Sagar Lonial 1,  Shi-Yong Sun 4
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
  • 2 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.
  • 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
  • 4 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: ssun@emory.edu.
PMID: 30059709 DOI: 10.1016/j.canlet.2018.07.033
Abstract

Agents that inhibit bromodomain and extra-terminal domain (BET) protein have been actively tested in the clinic as potential Anticancer drugs. Proteasome inhibitors such as carfilzomib (CFZ) are FDA-approved for the treatment of patients with advanced multiple myeloma and have been tested against other cancers. The current study focuses on the combination of a BET inhibitor (e.g., JQ1) and a Proteasome Inhibitor (e.g., CFZ) as a novel Cancer therapeutic strategy and the underlying mechanisms. The tested combination (JQ1 with CFZ) synergistically decreased cell survival and enhanced Apoptosis in vitro and inhibited tumor growth in vivo. The dramatic induction of Apoptosis was accompanied by enhanced elevation of Bim and ER stress. Bim knockout significantly attenuated Apoptosis induced by the combination, suggesting a critical role of Bim induction in mediating the enhanced induction of Apoptosis by BET and Proteasome co-inhibition. The combination significantly increased Bim mRNA levels with limited effect on Bim protein stability, suggesting a primary transcriptional regulation of enhanced Bim expression. Our findings warrant further investigation of this combinatorial strategy as an effective regimen against Cancer in the clinic.

Keywords

Apoptosis; BET; Bim; Cancer; Proteasome.

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