Chronic hypoxia induces androgen-independent and invasive behavior in LNCaP human prostate cancer cells

Purpose: Tumor hypoxia is a common feature of any cancer, including prostate cancer (CaP), and associated with tumor cell aggressiveness. Although some reports are available on acute hypoxia-response in CaP cells aggressiveness, little is known about chronic hypoxia-response. We investigated the effects of chronic hypoxia on human CaP cells. Materials and methods: The human androgen-dependent CaP cell line LNCaP was cultured under normoxia (21% O-2), acute hypoxia (1% O-2), or chronic hypoxia (1% O-2 for over 6 months). The cell growth, cell cycle and cell behavior of these cells were analyzed by cell count, flow cytornetric analysis and in vitro cell migration and invasion assay, respectively. The expression of matrix metalloproteinases and intracellular signaling pathways were tested by real time reverse transcriptase-polymerase chain reaction and Western blotting. Results: Chronic hypoxia-conditioned LNCaP cells grew in an androgen-independent manner with acceleration of G1 to S phase cell cycle progression. Chronic hypoxia, but not acute hypoxia, accelerated cell migration and invasion. The expressions of matrix metalloproteinase-7, -9, -14, and -15 were significantly up-regulated in LNCaP cells under chronic hypoxia, but not under acute hypoxia. In addition, PI3K/Akt, JAK/STAT, and HIF-1 pathways were activated in chronic hypoxia-conditioned LNCaP cells. Conclusions: These results suggested that chronic hypoxia plays an important role in enhancement of malignant potential during androgen-independent CaP progression. (C) 2013 Elsevier Inc. All rights reserved.