Abstract 4719: Modulation of HR-HPV viral protein E7 by SHetA2 in cervical cancer

Abstract

Abstract Introduction: The purpose of this study is to determine the effect of the chemotherapeutic sulfur heteroarotinoid A2 (SHetA2) on high-risk human papillomavirus (HR-HPV) proteins and the modulation of cell survival and proliferation in cervical cancer. Cervical cancer is caused by persistent HR-HPV infection. HR-HPV tumorigenesis is driven by its early 6 and 7 (E6, E7) oncoproteins, which increase cell proliferation and survival. Cellular pathways regulated by E6 and E7 are counter-regulated by the investigational new drug SHetA2, which is currently in phase 1 clinical trial for advanced and recurrent cancers. SHetA2 disrupts complexes of 70-kDa heat shock protein (HSP70) family members, hsc70, GRP78, and mortalin, with their client proteins. We hypothesized that SHetA2 reduces E6 and E7 levels and their binding to HSP70 chaperones in association with the reduction of cervical cancer cells and tumor growth. Methods: SHetA2 effects on specific genes and proteins in HR-HPV-positive cervical cancer cell lines and xenograft tumors were assessed by western blot, quantitative polymerase chain reaction, immunofluorescence ligation assays, and coimmunoprecipitation assays. Results: SHetA2 significantly reduced E6 and E7 mRNA, and protein levels of E7 and the E7-regulated p16, but not E6 in cervical cancer cells and xenograft tumors. MG132 inhibition of proteasome function attenuated the E7 reduction. HSP70/hsc70 proteins bound E7 and SHetA2 disrupted these complexes. Conclusions/Implications: SHetA2 reduces E7 proteins in cervical cancer cells through a mechanism that involves proteasomal degradation in association with disruption of HSP70/E7 complexes, p16 reduction, and decreased cell and tumor growth. This is the first demonstration of HSP70/E7 complexes. SHetA2-induced release of E7 from HSP70s could be causing increased susceptibility of E7 to proteasomal degradation. This data supports the development of SHetA2 and HSP70 inhibitors for cervical cancer. Citation Format: Justin Garland, Showket Hussain, Doris M. Benbrook. Modulation of HR-HPV viral protein E7 by SHetA2 in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4719.