Carcinogenesis Advance Access published online on September 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh274
© 2004 by Oxford University Press
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1 The Department of Pathology, The University of Calgary; The Department of Oncology, The University of Calgary; The Department of Medical Biochemistry, The University of Calgary
* To whom correspondence should be addressed. E-mail: demetric{at}ucalgary.ca.
Flow cytometric analysis of fibroblasts, normal breast epithelial cells and breast or other cancer cell lines identified variation in the abilities of cell lines to undergo cell cycle arrest as a response to hypoxia. Human mammary epithelial cells (HMEC), normal fibroblasts (Hs68 and WI38), HeLa cervical carcinoma and HTB-30 breast carcinoma cells arrest in G1/S in response to severe hypoxia. Hep3B hepatocellular carcinoma cells did not exhibit orderly G1/S arrest in response to severe hypoxia. We found a general decrease in p16 mRNA levels, with an associated decrease in p16 protein levels in both normal cells and in cancer cells, regardless of their cell cycle response to hypoxia. p27 protein levels did not correlate with the cell line's ability to enter a hypoxic G1/S arrest. Furthermore, cell lines that underwent G1/S arrest showed decreased expression of HIF-1a and at least one member of INK4 or Sdi CDKI families after 12-24 hours of hypoxia. Conversely, Hep3B, which did not exhibit orderly hypoxia-associated G1/S arrest, also did not show decreased HIF-1a, INK4 or Sdi protein levels in hypoxia. Furthermore, Hep3B showed constitutive activating phosphorylation of Akt and inhibitory phosphorylation of GSK3
Revised August 11, 2004
Accepted August 23, 2004
CANCER BIOLOGY
Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines
2 The Department of Pathology, The University of Calgary; The Department of Oncology, The University of Calgary; The Department of Medical Biochemistry, The University of Calgary; Calgary Laboratory Services, The University of Calgary
Abstract 
, which was the opposite pattern to that exhibited by the cell lines showing the G1/S arrest phenotype. Inhibition of GSK3 by lithium chloride treatment of HeLa cells converted the HIF-1a, p16 and p27 loss to levels unchanged by hypoxic exposure. Our results suggest that regulation of the cell cycle during hypoxia in either normal or cancer cells is not simply due to upregulation of cell cycle kinase inhibitors. Furthermore, decreased protein expression of HIF-1a, p16 and p27 was associated with both a hypoxia-induced G1/S arrest phenotype and increased GSK3 activity..
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