TY - JOUR
T1 - p38α blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1α- to FoxO-dependent transcription
AU - Chiacchiera, F.
AU - Matrone, A.
AU - Ferrari, E.
AU - Ingravallo, G.
AU - Lo Sasso, G.
AU - Murzilli, S.
AU - Petruzzelli, M.
AU - Salvatore, L.
AU - Moschetta, A.
AU - Simone, C.
N1 - Funding Information:
This work was partially supported by a ‘My First Grant’ (to CS) and a ‘Start-Up Grant’ (to AM) from the Italian Association for Cancer Research and by a grant from ‘Fondazione Negri Sud ONLUS’ (to CS). CS is grateful to his wife Viviana for continuous encouragement and support.
Funding Information:
Acknowledgements. We thank Dr. Francesco Paolo Jori for his helpful discussion during the preparation of the manuscript and editorial assistance and Dr. Nicola Martelli for technical assistance. Dr. Chiacchiera and Dr. Matrone are supported by FIRC (Italian Foundation for Cancer Research) and AIRC (Italian Association for Cancer Research) fellowships, respectively.
PY - 2009
Y1 - 2009
N2 - Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38α activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38α sustains the expression of HIF1α target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38α triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38α inhibits CRC growth in xenografted nude mice and azoxymethane-treated ApcMin mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38α affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.
AB - Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38α activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38α sustains the expression of HIF1α target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38α triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38α inhibits CRC growth in xenografted nude mice and azoxymethane-treated ApcMin mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38α affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.
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U2 - 10.1038/cdd.2009.36
DO - 10.1038/cdd.2009.36
M3 - Article
C2 - 19343039
AN - SCOPUS:69049096002
SN - 1350-9047
VL - 16
SP - 1203
EP - 1214
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 9
ER -