TY - JOUR
T1 - Targeted therapy against chemoresistant colorectal cancers
T2 - Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A
AU - Germani, Aldo
AU - Matrone, Antonio
AU - Grossi, Valentina
AU - Peserico, Alessia
AU - Sanese, Paola
AU - Liuzzi, Micaela
AU - Palermo, Rocco
AU - Murzilli, Stefania
AU - Campese, Antonio Francesco
AU - Ingravallo, Giuseppe
AU - Canettieri, Gianluca
AU - Tezil, Tugsan
AU - Simone, Cristiano
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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.
AB - 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.
KW - Cell death
KW - Chemoresistance
KW - Colorectal cancer
KW - Dual therapy
KW - P38 MAPK
UR - http://www.scopus.com/inward/record.url?scp=84893131728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893131728&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2013.10.035
DO - 10.1016/j.canlet.2013.10.035
M3 - Article
C2 - 24215867
AN - SCOPUS:84893131728
VL - 344
SP - 110
EP - 118
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 1
ER -