Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A

Aldo Germani, Antonio Matrone, Valentina Grossi, Alessia Peserico, Paola Sanese, Micaela Liuzzi, Rocco Palermo, Stefania Murzilli, Antonio Francesco Campese, Giuseppe Ingravallo, Gianluca Canettieri, Tugsan Tezil, Cristiano Simone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)110-118
Number of pages9
JournalCancer Letters
Volume344
Issue number1
DOIs
Publication statusPublished - Mar 1 2014

Keywords

  • Cell death
  • Chemoresistance
  • Colorectal cancer
  • Dual therapy
  • P38 MAPK

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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