P110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Carolina Torres*, Georgina Mancinelli, Jose Cordoba-Chacon, Navin Viswakarma, Karla Castellanos, Sam Grimaldo, Sandeep Kumar, Daniel Principe, Matthew J. Dorman, Ronald McKinney, Emilio Hirsch, David Dawson, Hidayatullah G. Munshi, Ajay Rana, Paul J. Grippo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

Original languageEnglish (US)
Pages (from-to)14724-14733
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number29
DOIs
StatePublished - 2019

Keywords

  • AKT signaling
  • Hepatotoxicity
  • High-fat diet
  • PI3Kg
  • Pancreatic cancer

ASJC Scopus subject areas

  • General

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