Novel proteasome inhibitor delanzomib sensitizes cervical cancer cells to doxorubicin-induced apoptosis via stabilizing tumor suppressor proteins in the p53 pathway
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Kevin Y. Guo1,2, Lili Han1,3, Xinyu Li2, Andrew V. Yang2, Jiaxiong Lu2, Shan Guan2, Hui Li1, Yang Yu2, Yanling Zhao2, Jianhua Yang2 and Hong Zhang1,4
1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Gynecology, People’s Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang 830001, China
4Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Hong Zhang, email: email@example.com
Keywords: cervical cancer; proteasome; delanzomib; doxorubicin; p53
Received: October 17, 2017 Accepted: November 28, 2017 Published: December 12, 2017
Cervical cancer, the third most commonly occurring cancer, is the second leading cause of cancer related mortality among women. Aberrant ubiquitination and proteasome activity, both human papillomavirus and tumor derived, have been shown to contribute to tumor angiogenesis, proliferation, and invasion in many cancers, including cervical cancer. Thus, small molecule proteasome inhibitors are a potential and strategic treatment option for cervical cancer. In this study, novel proteasome inhibitor delanzomib (CEP-18770) exhibited potent pro-apoptotic and cytotoxic effects on a panel of cervical cancer cell lines by blocking proteasomal activity. Delanzomib also significantly sensitized cervical cancer cells to treatment of doxorubicin (Dox), a traditional chemotherapeutic agent. Furthermore, proteasome inhibition revealed stabilization of p53 and p53 transcriptional targets and induction of p38/JNK phosphorylation. Additionally, delanzomib worked synergistically with Dox to further upregulate p53 and its downstream targets and enhanced Dox-induced p38 phosphorylation. Our study strongly supports the 26S proteasome as a potential therapeutic target in cervical cancer and proteasome inhibition by delanzomib may be a potential treatment strategy for cervical cancer patients.
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