A mathematical model of HiF-1α-mediated response to hypoxia on the G1/S transition

Hypoxia is known to influence the cell cycle by increasing the G1 phase duration or by inducing a quiescent state (arrest of cell proliferation). This entry into quiescence is a mean for the cell to escape from hypoxia-induced apoptosis. It is suggested that some cancer cells have gain the advantage over normal cells to easily enter into quiescence when environmental conditions, such as oxygen pressure, are unfavorable [43,1]. This ability contributes in the appearance of highly resistant and aggressive tumor phenotypes [2]. The HiF-1 alpha factor is the key actor of the intracellular hypoxia pathway. As tumor cells undergo chronic hypoxic conditions, HiF-1 alpha is present in higher level in cancer than in normal cells. Besides, it was shown that genetic mutations promoting overstabilization of HiF-1 alpha are a feature of various types of cancers [7]. Finally, it is suggested that the intracellular level of HiF-1 alpha can be related to the aggressiveness of the tumors [53,24,4,10]. However, up to now, mathematical models describing the G1/S transition under hypoxia, did not take into account the HiF-1 alpha factor in the hypoxia pathway. Therefore, we propose a mathematical model of the G1/S transition under hypoxia, which explicitly integrates the HiF-1 alpha pathway. The model reproduces the slowing down of G1 phase under moderate hypoxia, and the entry into quiescence of proliferating cells under severe hypoxia. We show how the inhibition of cyclin D by HiF-1 alpha can induce quiescence; this result provides a theoretical explanation to the experimental observations of Wen et al. (2010) [50]. Thus, our model confirms that hypoxia-induced chemoresistance can be linked, for a part, to the negative regulation of cyclin D by HiF-1 alpha. (C) 2013 Elsevier Inc. All rights reserved.