Journal Article

Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

Okuyama, Hiroaki, Ohue, Masayuki, Inoue, Masahiro, Endo, Hiroko

2014

Overview

A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to 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, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AKT protein / Apoptosis / ATP / Biochemistry / Biotechnology / Cancer / Cancer cells / Cell culture / Cell cycle / Cell death / Cell growth / Cell Hypoxia / Cell Line, Tumor / Cell proliferation / Cell Survival / Chemotherapy / Chronic illnesses / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - pathology / Dormancy / Down-Regulation / Drug Resistance, Neoplasm / Energy demand / Energy Metabolism / Enzyme Activation / Gene expression / Health aspects / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Intercellular Signaling Peptides and Proteins - deficiency / Intracellular Space - metabolism / Kinases / Malignancy / Medicine and Health Sciences / Metabolism / Oxygen / Pancreatic cancer / Pancreatic Neoplasms - pathology / Phosphorylation / Protein synthesis / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Radiation therapy / Regulatory mechanisms (biology) / Rodents / Signal Transduction / Studies / Time Factors / Tumor cell lines / Tumor cells / Tumor Microenvironment / Tumors