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Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

Oncogene volume 25, pages 917–928 (2006)Cite this article

Abstract

Low oxygen tension (hypoxia) is a common feature of solid tumors and stimulates the expressions of a variety of genes including those related to angiogenesis, apoptosis and endoplasmic reticulum (ER) stress response. Here we show a close correlation between metastatic potential and the resistance to hypoxia- and ER stress-induced apoptosis among the cell lines with differing metastatic potential derived from Lewis lung carcinoma. An apoptosis-specific expression profiling and immunoblot analyses revealed that the expression of antiapoptotic Mcl-1 increased as the resistance to apoptosis increased. Downregulation of the Mcl-1 expression in the high-metastatic cells by Mcl-1 small interfering RNA increased the sensitivity to hypoxia-induced apoptosis and decreased the metastatic ability. The hypoxia-induced apoptosis was not associated with p53 accumulation, although at present it is not possible to conclude that apoptosis-induced apoptosis is p53-independent. There was no correlation between the expression levels of ER stress-response proteins GADD153, GRP78 and ORP150 and the resistance to hypoxia or ER stresses. In vitro, small numbers of the high-metastatic cells overtook the low-metastatic cells after exposure to several rounds of hypoxia and reoxygenation. In solid tumors initially established from equal mixtures, the proportion of the high-metastatic cells to low-metastatic cells was significantly higher in hypoxic areas. Moreover, the high-metastatic cells were overtaking the low-metastatic cells in some of the tumors. Thus, tumor hypoxia and ER stress may provide a physiological selective pressure for the expansion of the high-metastatic cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors.

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Acknowledgements

We thank the National Cancer Institute (CTEP) for providing EF5. This work was supported in part by Grant-in-Aid from the Ministry of Health, Labour, and Welfare for Third Term Comprehensive Control Research for Cancer and from the Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Division of Chemotherapy, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan

    N Koshikawa, C Maejima & K Takenaga

  2. Division of Pathology, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan

    N Koshikawa

  3. Division of Biochemistry, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan

    K Miyazaki & A Nakagawara

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Correspondence to K Takenaga.

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Koshikawa, N., Maejima, C., Miyazaki, K. et al. Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors. Oncogene 25, 917–928 (2006). https://doi.org/10.1038/sj.onc.1209128

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