Abstract
Abstract In our previous research we characterized novel ALDH1A inhibitors (1A1, 1A2, 1A3) 673A that specifically target Ovarian Cancer Stem cells (OvCSC) and trigger cell programmed necrosis (necroptosis). Following ALDH1A inhibition CD133+ (A2780) FACS sorted cells we detected increase in phospho LKB1 while its major downstream target AMPKa did not exhibit changes in phosphorylation level. In addition to AMPKa, which is most known downstream target of LKB1, there are 11 AMPKa-like proteins that can be phosphorylated by LKB1. These proteins have been studied mostly in brain development. To detect AMPKa-like relevancy to high grade serous ovarian cancer, we next analyzed TCGA data. Surprisingly we identified many alterations in all 12 genes, including LKB1 (STK11). We only focused on alterations that exhibit gene amplifications or mRNA upregulation. Based on TCGA data, all AMPKa-like genes have many alterations in ovarian tumors suggesting importance of these genes to ovarian cancer tumorigenesis. We next continued to analyze combinations of any two genes to test their co-occurrence or mutual exclusivity. We detected 9 gene combinations, in which amplification or mRNA upregulation in AMPKa-like genes co-occur (p<0.5) in patient tumors. We next validated expression of AMPKa-like genes in ovarian cancer cell lines and confirmed their expression in PEO-4, Ovcar8, and Ovsaho. We next treated Ovsaho, PEO4 and OvCAR8 cells with ALDH1A inhibitor 673A for 8 and 14 hr, and profiled expression of AMPKa-like genes following ALDH1A inhibition. We detected significant changes in AMPKa-like genes, suggesting their role in cell programmed necrosis. To confirm our bioinformatic findings, we established cell lines that mimic patient tumors with most frequent co-occurrence of AMPKa genes. We have been studying these cell lines in terms of cell proliferation, stemness and role in cell death. Citation Format: Anmbreen Jamroze, Mikhail Chesnokov, Ilana Chefetz. AMPKA-LIKE PROTEINS IN OVARIAN CANCER TUMORIGENESIS AND NECROPTOSIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-064.
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