Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells

BACKGROUND. Androgen withdrawal, the standard therapeutic strategy for advanced prostate cancer, induces a rapid reduction of blood flow to prostate and prostate cancer tissues and the concomitant onset of a hypoxic environment in these tissues. To establish whether hypoxia-responsiveness (by means of the action of hypoxia inducible factor [HIF] -1alpha protein) might affect the tumorigenic or survival properties of prostate cancer cells, we studied how acute exposure of cultured human prostate cancer cells (LNCaP cell line) to hypoxia might alter their pattern of gene expression and their in vitro behavior, METHODS. LNCaP cultures were placed in a hypoxia chamber for Lip to 24 hr and were compared with control (normoxic) cells for the expression of gene products by Western blotting and semiquantitative reverse transcription-polymerase chain reaction techniques. RESULTS. Exposure of LNCaP cells to acute hypoxia activated a typical Cellular hypoxia response characterized by up-regulation of HIF-1alpha and vascular endothelial growth factor protein expression. In contrast, expression of differentiation-specific proteins (prostate specific antigen and androgen receptor) or proliferative-regulatory proteins (c-myc, cyclin D1, p27) were down-regulated by hypoxia. Some of these latter changes (reduction of c-myc and cyclin D expression) were not accompanied by corresponding reduction of mRNAs and were abrogated by a proteosome inhibitor (MG132), suggesting that their loss was associated with their increased degradation rather than through transcriptional controls. The phosphorylation of Akt/protein kinase B and its downstream target, forkhead protein, was highly up-regulated by hypoxia, and cells exposed to transient periods of hypoxia became significantly less sensitive to an apoptotic stimulus (exposure to phorbol ester) when compared with normoxic cells. CONCLUSION. This study demonstrates that even acute hypoxia has the potential to drastically alter the growth, differentiation characteristics, and apoptotic sensitivity of a prostate cancer cell. (C) 2002 Wiley-Liss, Inc.