Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells.
Solid tumor cells are often exposed to hypoxia in vivo, which has been suggested to promote genetic instability in those cells. Telomere elongation by telomerase is implicated in chromosome stabilization in immortal cells. Here we found that hypoxia enhanced telomerase activity in the solid tumor A2780 and HT-29 cells but not in the leukemia U937 cells. The telomerase activation correlated with activation of mitogen-activated protein kinase (MAPK) and c-fos expression. The MEK1 inhibitor PD98059 repressed telomerase activation in the hypoxic cells. Consistently, a dominant negative MEK1 inhibited telomerase activation by hypoxia. Finally, we found a good correlation between telomerase activation and resistance to apoptotic cell death under hypoxic conditions. These findings indicate that hypoxia up-regulates telomerase activity via MAPK cascade signaling especially in solid tumor cells and suggest that solid tumor cells might enhance the telomerase activity as a stress response against genotoxicity induced by hypoxia.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Tokyo, Toshima-ku, 170-8455, Japan.
H
H
Seimiya
M
M
Tanji
T
T
Oh-hara
A
A
Tomida
I
I
Naasani
T
T
Tsuruo
D017209:Apoptosis; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D015687:Cell Hypoxia; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017931:DNA Primers; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019098:Telomerase