TY - JOUR
T1 - Hypoxia-mediated up-regulation of pim-1 contributes to solid tumor formation
AU - Chen, Jian
AU - Kobayashi, Masanobu
AU - Darmanin, Stephanie
AU - Qiao, Yi
AU - Gully, Christopher
AU - Zhao, Ruiying
AU - Kondo, Satoshi
AU - Wang, Hua
AU - Wang, Huamin
AU - Yeung, Sai Ching Jim
AU - Lee, Mong Hong
N1 - Funding Information:
Supported by the NIHRO1CA (089266 M.H.L.), Grants-in-Aid for Scientific Research from Japan Society for the Promotion Science (J.C.), U. S. Department of Defense Breast Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs (DOD SIDA BC062166 S.J.Y. & M.H.L.) and Cancer Center Core Grant (CA16672).
PY - 2009/7
Y1 - 2009/7
N2 - 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.
AB - 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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U2 - 10.2353/ajpath.2009.080972
DO - 10.2353/ajpath.2009.080972
M3 - Article
C2 - 19528349
AN - SCOPUS:67649969176
SN - 0002-9440
VL - 175
SP - 400
EP - 411
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -