|
FOXO factor promotes survival of oxygen-deprived cancer cells
December 28, 2007Scientists report that an evolutionarily conserved transcription factor may have both positive and negative effects on the growth of tumors, depending on whether or not the tumor cells have enough oxygen. The research, published by Cell Press in the December 28th issue of Molecular Cell, provides critical new information about how normal cells and cancer cells survive under stress.
Dividing tumor cells are often deprived of oxygen as a result of their rapid expansion or aberrant blood vessels. Response to stressful low oxygen conditions, known as hypoxia, involves expression of several genes that enable cells to adapt to the oxygen deficit. This response is primarily mediated by the hypoxia-inducible transcription factors, HIF1 and HIF2.
HIF proteins play a key role in hypoxic tumor development and are often associated with poor patient prognosis. Hypoxic tumor cells exhibit decreased sensitivity to radiation and chemotherapy, and increased potential for invasion and metastasis. Interestingly, recent research findings have also revealed an anti-cancer role for HIF1 that is mediated by the initiation of programmed cell death, called apoptosis, in response to severe hypoxic stress. Although HIF1 has been linked to several pro-apoptotic target genes, specific mechanisms that regulate this particular function of HIF1 are not well understood.
Dr. Tak W. Mak from the Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital in Toronto and colleagues found that hypoxia stimulates an HIF1-dependent increase in a protein called FOXO3a. FOXO transcription factors are evolutionarily conserved proteins that are critical regulators of cell survival under stressful conditions. Recently, FOXO proteins have also been shown to act as tumor suppressors.
Dr. Mak's group observed that under hypoxic conditions, FOXO3a inhibited HIF-1 induced apoptosis in normal cells and breast cancer cells by stimulating the transcription of the HIF1 target gene CITED2. Activation of CITED2, known to exert a negative influence on HIF1 activity, resulted in reduced expression of pro-apoptotic HIF1 target genes.
"Our results reveal a pro-survival role for FOXO3a in normal cells and cancer cells that are adapting to hypoxic stress," explains Dr. Mak. "Targeting of this pathway may benefit cancer treatment. Tumorigenesis could possibly be inhibited by either very high levels of FOXO3a/CITED2 activity that would cause complete inhibition of HIF1 or very low levels that would permit HIF1- induced apoptosis under hypoxic stress."
Cell Press
Dr. Tak W. Mak from the Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital in Toronto and colleagues found that hypoxia stimulates an HIF1-dependent increase in a protein called FOXO3a. FOXO transcription factors are evolutionarily conserved proteins that are critical regulators of cell survival under stressful conditions. Recently, FOXO proteins have also been shown to act as tumor suppressors.
Dr. Mak's group observed that under hypoxic conditions, FOXO3a inhibited HIF-1 induced apoptosis in normal cells and breast cancer cells by stimulating the transcription of the HIF1 target gene CITED2. Activation of CITED2, known to exert a negative influence on HIF1 activity, resulted in reduced expression of pro-apoptotic HIF1 target genes.
"Our results reveal a pro-survival role for FOXO3a in normal cells and cancer cells that are adapting to hypoxic stress," explains Dr. Mak. "Targeting of this pathway may benefit cancer treatment. Tumorigenesis could possibly be inhibited by either very high levels of FOXO3a/CITED2 activity that would cause complete inhibition of HIF1 or very low levels that would permit HIF1- induced apoptosis under hypoxic stress."
Cell Press
Hypoxic News and Current Hypoxic Events RSSA new gene trigger for pregnancy disorder identified
The COMT gene - known already for its role in schizophrenia - has been found to play a role in preeclampsia, according to a report in today's advance on-line issue of Nature.
Researchers link master regulator of innate immunity to the hypoxic response
Survival of all animals depends on their ability to withstand microbial infections and adapt to fluctuations in oxygen concentrations.
Adaptive functional evolution of leptin in cold-adaptive pika family
Researchers at the Northwest Institute of Plateau Biology, Chinese Academy of Sciences have put forward the viewpoint for the first time that adaptive functional evolution may occur in the leptin protein of the pika (Ochotona) family, a typical cold-adaptive mammal.
Better access to cool caps improves outcomes, lowers cost of treating asphyxia in newborns
When newborns suffering from a form of asphyxia at birth have better access to head cooling devices, fewer will face a lifetime of debilitating and costly health complications, according to researchers at Beth Israel Deaconess Medical Center (BIDMC).
Link between chronic kidney disease and oxygen-deprived tissue
Researchers at the University of Pennsylvania School of Medicine have discovered how low-oxygen conditions can worsen chronic kidney disease (CKD).
A new chemotherapeutic target for hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a major health problem worldwide. Currently, the only chance for obtaining a cure in patients with HCC is by either a surgical resection or liver transplantation.
Increase in ethanol production from corn could significantly impact
If projected increases in the use of corn for ethanol production occur, the harm to water quality could be considerable, and water supply problems at the regional and local levels could also arise, says a new report from the National Research Council.
Low oxygen in coastal waters impairs fish reproduction
Low oxygen levels in coastal waters interfere with fish reproduction by disrupting the fishes' hormones, a marine scientist from The University of Texas at Austin Marine Science Institute has found.
Alternative farming cleans up water
Although the addition of nutrients to soil helps to maximize crop production, fertilizer can leach nutrients, polluting the water supply.
Hearts of male and female rainbow trout are different
The heart is one of the most energy demanding organs of the human body. Its failure to function properly accounts for 600,000 deaths each year. Similarly, the rainbow trout, native to the Pacific Northwest and beloved as a sport- and food fish, requires dynamic and sustained cardiac function to maintain its health and swimming activity.
More Hypoxic News Articles
| © 2008 BrightSurf.com |