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Abstract
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.
Highlights
The third most common cancer worldwide, cervical cancer ranks second in cancer related mortality among women [1, 2]
Proteasome inhibitor delanzomib exhibits cytotoxic effects on cervical cancer cells To evaluate efficacy, delanzomib was tested on five typical cervical cancer cell lines: human cervical cancer line (HeLa), SiHa, ME-180, C33A, and Caski cell lines
In a panel of 5 cervical cancer cell lines, a combination of initial protein levels of either p53, p21, PUMA, or Noxa were downregulated without treatment (Figure 2A, Supplementary Figure 1)
Summary
The third most common cancer worldwide, cervical cancer ranks second in cancer related mortality among women [1, 2]. With the cascade mechanism of three variable enzymes, E1, E2, and E3, the 26S proteasome in humans is provided with a recognition signal to degrade proteins that www.impactjournals.com/oncotarget have undergone specific ubiquitination [5]. Proteasome treatment offers possible pro- or anti-apoptotic effects induced via p38 and the c-Jun N-terminal kinase (JNK) pathway, notwithstanding the specific mechanisms are yet to be elucidated [10, 11]. As a positive side effect, lack of proteasomal degradation causes anti-tumor protein accumulation and induces a terminal unfolded protein response [12]. Studying proteasomal degradation is fundamental to cervical cancer as there seems to be no connection with the normative mutations of tumor suppressive genes found in many other cancers, prompting heavy causation due to proteasome-related faults [13]
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