Hypoxia-mediated up-regulation of Pim-1 contributes to solid tumor formation.
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.
Chen
Jian
J
Department of Surgical Oncology, Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Kobayashi
Masanobu
M
Darmanin
Stephanie
S
Qiao
Yi
Y
Gully
Christopher
C
Zhao
Ruiying
R
Kondo
Satoshi
S
Wang
Hua
H
Wang
Huamin
H
Yeung
Sai-Ching Jim
SC
Lee
Mong-Hong
MH
D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D054875:Ubiquitination; D015854:Up-Regulation
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1