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Frataxin participates to the hypoxia-induced response in tumors.

Guccini I, Serio D, Condò I, Rufini A, Tomassini B, Mangiola A, Maira G, Anile C, Fina D, Pallone F, Mongiardi MP, Levi A, Ventura N, Testi R, Malisan F - Cell Death Dis (2011)

Bottom Line: Frataxin is a protein required for cell survival since complete knockout is lethal.We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression.Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Biochemical Sciences, Laboratory of Signal Transduction, University Tor Vergata, Rome, Italy.

ABSTRACT
Defective expression of frataxin is responsible for the degenerative disease Friedreich's ataxia. Frataxin is a protein required for cell survival since complete knockout is lethal. Frataxin protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor. The molecular bases of this apparent paradox are missing. We therefore sought to investigate the pathways through which frataxin enhances stress resistance in tumor cells. We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression. Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53. Importantly, we show for the first time that frataxin is in fact increased in human tumors in vivo. These results show that frataxin participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression.

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HIFs mediate hypoxia-induced frataxin upregulation. Left panels: human glioblastoma cells TB10 (a), U87 (b) and U118 (c) wild type or stably interfered for HIF-1α (shHIF-1α) were exposed to severe hypoxia for 18 h and frataxin (Fxn), tubulin (Tub), HIF-1α and HIF-2α expression analyzed. Data are representative of four, three and three independent experiments for TB10, U87 and U118 cells, respectively. Right panels: densitometric quantification of frataxin upregulation. Frataxin expression was normalized with tubulin and frataxin expression in normoxia set to one. Data represent the mean±1 S.E.M. from the different independent experiments performed for cell lines described in left panels. P-values were calculated with Student's t-test: *P<0.05; **P<0.01
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fig2: HIFs mediate hypoxia-induced frataxin upregulation. Left panels: human glioblastoma cells TB10 (a), U87 (b) and U118 (c) wild type or stably interfered for HIF-1α (shHIF-1α) were exposed to severe hypoxia for 18 h and frataxin (Fxn), tubulin (Tub), HIF-1α and HIF-2α expression analyzed. Data are representative of four, three and three independent experiments for TB10, U87 and U118 cells, respectively. Right panels: densitometric quantification of frataxin upregulation. Frataxin expression was normalized with tubulin and frataxin expression in normoxia set to one. Data represent the mean±1 S.E.M. from the different independent experiments performed for cell lines described in left panels. P-values were calculated with Student's t-test: *P<0.05; **P<0.01

Mentions: HIFs are main mediators of hypoxia. Under low oxygen conditions, they translocate to the nucleus where they act as transcription factors for different HRE-containing genes. As murine frataxin was shown to possess an HRE for HIF-2α, we assessed whether frataxin upregulation in response to hypoxia in human cancer cells is mediated through the HIF pathway. We took advantage of glioblastoma cell lines TB10, U87 and U118, which stably express shRNA against HIF-1α, resulting in 70–80% knockdown of its expression.30 Wild-type cells and cells stably expressing shHIF-1α were subjected to hypoxia and frataxin expression was analyzed. As expected, on shRNA treatment, hypoxia-induced HIF-1α expression was significantly prevented in cells stably expressing shHIF-1α. Importantly, while HIF-2α expression was unchanged, the induction of frataxin on hypoxic stress was almost completely abolished (Figure 2). These results suggest that frataxin induction in response to hypoxia is controlled by HIF-1α in human cells.


Frataxin participates to the hypoxia-induced response in tumors.

Guccini I, Serio D, Condò I, Rufini A, Tomassini B, Mangiola A, Maira G, Anile C, Fina D, Pallone F, Mongiardi MP, Levi A, Ventura N, Testi R, Malisan F - Cell Death Dis (2011)

HIFs mediate hypoxia-induced frataxin upregulation. Left panels: human glioblastoma cells TB10 (a), U87 (b) and U118 (c) wild type or stably interfered for HIF-1α (shHIF-1α) were exposed to severe hypoxia for 18 h and frataxin (Fxn), tubulin (Tub), HIF-1α and HIF-2α expression analyzed. Data are representative of four, three and three independent experiments for TB10, U87 and U118 cells, respectively. Right panels: densitometric quantification of frataxin upregulation. Frataxin expression was normalized with tubulin and frataxin expression in normoxia set to one. Data represent the mean±1 S.E.M. from the different independent experiments performed for cell lines described in left panels. P-values were calculated with Student's t-test: *P<0.05; **P<0.01
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101705&req=5

fig2: HIFs mediate hypoxia-induced frataxin upregulation. Left panels: human glioblastoma cells TB10 (a), U87 (b) and U118 (c) wild type or stably interfered for HIF-1α (shHIF-1α) were exposed to severe hypoxia for 18 h and frataxin (Fxn), tubulin (Tub), HIF-1α and HIF-2α expression analyzed. Data are representative of four, three and three independent experiments for TB10, U87 and U118 cells, respectively. Right panels: densitometric quantification of frataxin upregulation. Frataxin expression was normalized with tubulin and frataxin expression in normoxia set to one. Data represent the mean±1 S.E.M. from the different independent experiments performed for cell lines described in left panels. P-values were calculated with Student's t-test: *P<0.05; **P<0.01
Mentions: HIFs are main mediators of hypoxia. Under low oxygen conditions, they translocate to the nucleus where they act as transcription factors for different HRE-containing genes. As murine frataxin was shown to possess an HRE for HIF-2α, we assessed whether frataxin upregulation in response to hypoxia in human cancer cells is mediated through the HIF pathway. We took advantage of glioblastoma cell lines TB10, U87 and U118, which stably express shRNA against HIF-1α, resulting in 70–80% knockdown of its expression.30 Wild-type cells and cells stably expressing shHIF-1α were subjected to hypoxia and frataxin expression was analyzed. As expected, on shRNA treatment, hypoxia-induced HIF-1α expression was significantly prevented in cells stably expressing shHIF-1α. Importantly, while HIF-2α expression was unchanged, the induction of frataxin on hypoxic stress was almost completely abolished (Figure 2). These results suggest that frataxin induction in response to hypoxia is controlled by HIF-1α in human cells.

Bottom Line: Frataxin is a protein required for cell survival since complete knockout is lethal.We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression.Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Biochemical Sciences, Laboratory of Signal Transduction, University Tor Vergata, Rome, Italy.

ABSTRACT
Defective expression of frataxin is responsible for the degenerative disease Friedreich's ataxia. Frataxin is a protein required for cell survival since complete knockout is lethal. Frataxin protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor. The molecular bases of this apparent paradox are missing. We therefore sought to investigate the pathways through which frataxin enhances stress resistance in tumor cells. We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression. Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53. Importantly, we show for the first time that frataxin is in fact increased in human tumors in vivo. These results show that frataxin participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression.

Show MeSH
Related in: MedlinePlus