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Proc Natl Acad Sci U S A. 2019 Jul 16;116(29):14724-14733. doi: 10.1073/pnas.1813012116. Epub 2019 Jul 2.

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity.

Author information

1
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612; ctp@ugr.es pgrippo@uic.edu.
2
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612.
3
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL 60612.
4
Research, Jesse Brown VA Medical Center, Chicago, IL 60612.
5
Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612.
6
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
7
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
8
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
9
Department of Medicine, Northwestern University, Chicago, IL 60611.

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.

KEYWORDS:

AKT signaling; PI3Kg; hepatotoxicity; high-fat diet; pancreatic cancer

PMID:
31266893
PMCID:
PMC6642408
[Available on 2020-01-02]
DOI:
10.1073/pnas.1813012116

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