Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-60407
Lohse, I. Elucidating the role of hypoxia-protective gene CPT1C in cell biology and carcinogenesis. 2011, University of Zurich, Faculty of Science.
The Carnitine Palmitoyltransferase 1c (CPT1C) has recently been identified as a p53-regulated brain-specific Carnitine Palmitoyltransferase (CPT) 1-family member. The CPT1-family of proteins regulates fatty acid oxidation at the step of fatty acid import into the mitochondria. Three CPT1 genes, demonstrating generalized tissue specificity, have been identified in mammals. The physiological roles of CPT1A, the prominent CPT1 gene in liver, and CPT1B, the prominent CPT1 gene in muscle, are well established due to their role in pathogenicity. In contrast, the physiological role of CPT1C remains elusive.
Although CPT1C expression is found in neurons throughout the entire brain, CPT1C expression is enriched in brain regions involved in the regulation of peripheral energy expenditure such as hypothalamus, amygdala and hippocampus. Hypothalamic feeding centers contain nutrient-sensitive neurons have been shown to regulate the desire for food intake and satiety in response to peripheral energy expenditure. The localization of CPT1C to brain, a tissue normally not using fatty acids as a primary energy source, suggests a potentially unique function for CPT1C.
Cpt1c knock-out mice have been reported to have a reduced body weight on a normal diet, but when fed a diet that is rich in fats, these mice demonstrate an increase in relative body weight concurrent with a reduction in both food intake and insulin resistance. The expression of CPT1C in the hypothalamic feeding centers combined with the metabolic phenotype displayed by knock-out mouse suggest for a regulatory role of CPT1C in peripheral energy sensing and energy homeostasis.
In addition to the role of CPT1C in normal brain, CPT1C has also been implicated in carcinogenesis. It has been demonstrated that CPT1C expression is induced by hypoxia and p53-stabilization. It has been shown previously, that CPT1C expression is increased in lung tumor samples if compared to normal tissue. Furthermore, cells depleted from CPT1C display a significant reduction in cell proliferation in response to hypoxia.
The results presented here show that CPT1C expression is regulated by the presence of an upstream open reading frame (uORF) located the 5´UTR of the CPT1C mRNA. The presence of one or more uORFs is conserved in CPT1C mRNAs of different species but not within the CPT1 family of proteins. We showed that CPT1C expression is repressed by the presence of the uORF in the feeding state. This translational repression is released in response to reduced energy availability and AMPK activity. Our results furthermore show that the translation of the main ORF is also derepressed in response to Palmitate-BSA treatment. These results further support the hypothesis suggesting that CPT1C plays an important role in the nervous system control of energy homeostasis and peripheral energy expenditure although the involved signaling cascades still need to be established.
We observed that CPT1C expression was also induced in response to HIV infection. HIV has been shown to remodel the host cell mechanism to facilitate virus production, which leads to increased β-oxidation rates. Induction of CPT1C expression in response to virus infection might be used to remodel cell metabolism in order to facilitate the production of new viruses.
Furthermore, we were able to show that the induction of CPT1C in response to hypoxia was mediated by the Hypoxia-inducible factor (HIF) and that CPT1C expression correlates with the HIF target PGK in pediatric brain tumors. We showed that constitutive expression of CPT1C results in increased levels of cell proliferation and motility in established breast and brain cancer cell lines. Down regulation of CPT1C using shRNAs reduced cell proliferation and motility. In contrast to the metastatic phenotype that was observed under normoxic and hypoxic conditions, the reduction in cell proliferation was only in response to hypoxia. Cancer cell proliferation and metastasis in the hypoxic zone of solid tumors are mainly controlled by the HIF transcription factor complex. Induction of CPT1C expression in response to tumor hypoxia might present a survival mechanism for hypoxic tumor cells. Our results add further evidence to the hypothesis that CPT1C contributes to metabolic adaptation of tumor cells in response to hypoxia. Activation of CPT1C in response to tumor hypoxia might lead to the activation of downstream pathways that serve to protect the cancer cells from metabolic stress. Further studies are necessary to establish the molecular function of CPT1C and the underlying signaling cascades.
Understanding the role of CPT1C in cancer cell metabolism might lead to the development of new approaches for the treatment hypoxic tumors.
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|Referees:||Hengartner M, Zaugg K, Krek W, Mak T|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology|
|DDC:||610 Medicine & health|
|Deposited On:||25 Feb 2012 20:32|
|Last Modified:||17 Oct 2012 02:49|
|Number of Pages:||101|
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