Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A.
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.
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy.
Aldo
A
Germani
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy.
Antonio
A
Matrone
Cancer Genetics Laboratory, IRCCS S. de Bellis, 70013 Castellana Grotte, Italy.
Valentina
V
Grossi
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy.
Alessia
A
Peserico
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy.
Paola
P
Sanese
Division of Pathological Anatomy, DETO, University of Bari, 70124 Bari, Italy.
Micaela
M
Liuzzi
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
Rocco
R
Palermo
Animal Care Facility, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy.
Stefania
S
Murzilli
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
Antonio Francesco
AF
Campese
Division of Pathological Anatomy, DETO, University of Bari, 70124 Bari, Italy.
Giuseppe
G
Ingravallo
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
Gianluca
G
Canettieri
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy. Electronic address: teziltugsan@sabanciuniv.edu.
Tugsan
T
Tezil
Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Ch), Italy; Division of Medical Genetics, DIMO, University of Bari, 70124 Bari, Italy. Electronic address: cristiano.simone@uniba.it.
Cristiano
C
Simone
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy / Q000379:methods*; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D048308:Mitogen-Activated Protein Kinase 14; D002945:Cisplatin
Cell death; Chemoresistance; Colorectal cancer; Dual therapy; p38 MAPK