Abstract 495: Inactive status of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia

Abstract

Abstract A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to the recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, which is exceptionally able to survive for weeks under hypoxic conditions (1%O2) without changing medium at all, while most of the tested cancer cell lines died after several days under these conditions. Under hypoxic conditions, the AsPC-1 cells entered an “inactive status” characterized by no proliferation or death and by metabolic suppression. They recovered to active status after being placed again in optimal culture conditions. Under chronic hypoxia, ATP turnover, an indicator of energy demand, was markedly decreased, as was AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro. Xenograft tumors generated with AKT over-expressing cells showed remarkable decrease of inactive zone, where BrdU uptake and S6 phosphorylation were eliminated without any sign of cell death. We recently developed a novel culture system for primary cancer cells. In contrast to most cancer cell lines, primary colorectal cancer cells entered inactive status with AKT suppression under hypoxia combined with growth factor-depleted conditions. The ability of cancer cells to survive in a deteriorated microenvironment by entering into an inactive status might be a common property among cancer cells. The cancer cells in inactive status of both primary cultured cancer cells and AsPC-1 cells were resistant to chemotherapy. Targeting the regulatory mechanism inducing this inactive status might provide a new strategy for overcoming resistance to various cancer therapies. Citation Format: Masahiro Inoue, Hiroaki Okuyama, Hiroko Endo, Masayuki Ohue. Inactive status of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 495. doi:10.1158/1538-7445.AM2014-495