Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines

Box, Adrian; Demetrick, Douglas J.

doi:10.1093/carcin/bgh274

Cited by 62 publications

(58 citation statements)

References 62 publications

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“…2). These results together with the observation that hypoxia induces G 1 arrest in various cancer cells (41,42) suggest that a considerable population of cells in the metastatic foci in vivo may be under G 1 arrest presumably because of insufficient nutritional states and/or relatively low O 2 concentrations (17). Considering that most of anticancer chemotherapeutic agents target cells in S or G 2 -M phases, rendering tumor cells under G 1 phase highly active in glycolysis and proliferative may cause increasing sensitivity to drugs by passing these cells through the metabolic checkpoint to undergo S and G 2 -M phases.…”

Section: Discussionsupporting

confidence: 69%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 69%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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“…The second mechanism relies on sequestration of c-Myc and subsequent induction of the cell-cycle inhibitors p21 and p27 (33). The mechanism by which certain cancer cell lines maintain proliferation while expressing HIF-1α protein has been a subject of investigation and did not seem to correlate with levels of HIF-1α, p21, or p27 levels (44). Previous studies have suggested that HIF-2α may promote cellular proliferation, with the relative balance between HIF-2α and HIF-1α determining the response to hypoxia (48).…”

Section: (D and E) Mouse Mefs Frommentioning

confidence: 99%

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi¹,

Gilkes

Hu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions. cell proliferation | chaperone mediated autophagy | lysosome

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“…Indeed, this phenomenon was not observed in the majority of tumor cells [32,39]. Besides, it is not clear that p27 is necessary to induce hypoxia-induced cell cycle arrest [6,21].…”

mentioning

confidence: 96%

“…Notably, the upregulation of cyclins inhibitors, such as p21 and p27, are reported [17,22,20]. However, some authors showed that the action of HiF-1α on p27 is not so clear since the expression of p27 under hypoxia may be independent of HiF-1α [6,9].…”

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confidence: 99%

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

Bedessem

Stéphanou

2014

Mathematical Biosciences

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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-1α factor is the key actor of the intracellular hypoxia pathway.As tumor cells undergo chronic hypoxic conditions, HiF-1α is present in higher level in cancer than in normal cells. Besides, it was shown that genetic mutations promoting overstabilization of HiF-1α are a feature of various types of cancers [8]. Finally, it is suggested that the intracellular level of HiF-1α 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-1α factor in the hypoxia pathway.Therefore, we propose a mathematical model of the G1/S transition under hypoxia, which explicitly integrates the HiF-1α 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-1α can induce quiescence; this result provides a theoretical explanation to the experimental observations of Wen et al. (2010). Thus, our model confirms that hypoxia-induced chemoresistance can be linked, for a part, to the negative regulation of cyclin D by HiF-1α.

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Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines

Cited by 62 publications

References 62 publications

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

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

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