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Originally published online as doi:10.2353/ajpath.2009.080972 on June 15, 2009

Published online before print June 15, 2009
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(American Journal of Pathology. 2009;175:400-411.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080972

Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation

Jian Chen*{dagger}{ddagger}, Masanobu Kobayashi§, Stephanie Darmanin*, Yi Qiao*{ddagger}, Christopher Gully{ddagger}, Ruiying Zhao{ddagger}, Satoshi Kondo{dagger}, Hua Wang, Huamin Wang||, Sai-Ching Jim Yeung**{dagger}{dagger} and Mong-Hong Lee{ddagger}

From the Divisions of Cancer-Related Genes,* and Cancer Biology,§ Institute for Genetic Medicine, and the Department of Surgical Oncology,{dagger} Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan; and the Departments of Molecular and Cellular Oncology,{ddagger} GI Medical Oncology, Pathology,|| Endocrine Neoplasia and Hormonal Disorders,** and General Internal Medicine,{dagger}{dagger} Ambulatory Treatment and Emergency Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Tumor hypoxia directly promotes genomic instability and facilitates cell survival, resulting in tumors with a more aggressive phenotype. The proto-oncogene pim-1 regulates apoptosis and the cell cycle by phosphorylating target proteins. Overexpression of Pim-1 can cause genomic instability and contribute to lymphomagenesis. It is not clear whether Pim-1 is involved in hypoxia-mediated tumor survival in solid tumors. Here, we show that hypoxia can stabilize Pim-1 by preventing its ubiquitin-mediated proteasomal degradation and can cause Pim-1 translocation from the cytoplasm to the nucleus. Importantly, overexpression of Pim-1 increases NIH3T3 cell transformation exclusively under hypoxic conditions, suggesting that Pim-1 expression under hypoxia may be implicated in the transformation process of solid tumors. Also, blocking Pim-1 function by introduction of dominant negative Pim-1 resensitizes pancreatic cancer cells to apoptosis induced by glucose-deprivation under hypoxia. Introduction of short interfering RNAs for Pim-1 also resensitizes cancer cells to glucose deprivation under hypoxic conditions, while forced overexpression of Pim-1 causes solid tumor cells to become resistant to glucose deprivation. Moreover, dominant negative Pim-1 reduces tumorigenicity in pancreatic cancer cells and HeLa xenograft mouse models. Together, our studies indicate that Pim-1 plays a distinct role in solid tumor formation in vivo, implying that Pim-1 may be a novel target for cancer therapy.






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