Title of article :
Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A
Author/Authors :
Germani، نويسنده , , Aldo and Matrone، نويسنده , , Antonio and Grossi، نويسنده , , Valentina and Peserico، نويسنده , , Alessia and Sanese، نويسنده , , Paola and Liuzzi، نويسنده , , Micaela and Palermo، نويسنده , , Rocco and Murzilli، نويسنده , , Stefania and Campese، نويسنده , , Antonio Francesco and Ingravallo، نويسنده , , Giuseppe and Canettieri، نويسنده , , Gianluca and Tezil، نويسنده , , Tugsan and Simone، نويسنده , , Cristiano، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2014
Pages :
9
From page :
110
To page :
118
Abstract :
Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38α is the main p38 isoform in CRC cells. Here we show that p38α pharmacological inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor protein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38-FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker.
Keywords :
Dual therapy , Chemoresistance , Colorectal Cancer , cell death , p38 MAPK
Journal title :
Cancer Letters
Serial Year :
2014
Journal title :
Cancer Letters
Record number :
1824202
Link To Document :
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