Abstract
The signaling pathways that mediate the development of pancreatic ductal adenocarcinoma (PDAC) downstream of mutant Kras remain incompletely understood. Here, we focus on ribosomal protein S6 (rpS6), an mTOR effector not implicated previously in cancer. Phosphorylation of rpS6 was increased in pancreatic acinar cells upon implantation of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or transgenic expression of mutant Kras. To examine the functional significance of rpS6 phosphorylation, we used knockin mice lacking all five phosphorylatable sites in rpS6 (termed rpS6(P-/-) mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6(P-/-) mice. The rpS6 mutants expressing oncogenic Kras showed increased p53 along with increased staining of γ-H2AX and 53bp1 (Trp53bp1) in areas of acinar ductal metaplasia, suggesting that rpS6 phosphorylation attenuates Kras-induced DNA damage and p53-mediated tumor suppression. These results reveal that rpS6 phosphorylation is important for the initiation of pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human cancers
Rapamycin attenuates the development of pancreatic cancer induced by chemical carcinogenesis To study the downstream effectors of PTEN in the development of pancreatic cancer in vivo, we first tested the effect of rapamycin, a clinically used selective inhibitor of mTOR complex1 (mTORC1)
As shown previously [36], implantation of beads soaked with DMBA into the body of the pancreas led to the development of pancreatic intraepithelial neoplasia (PanIN) lesions within 3 to 4 weeks (Fig. 1A–C), which resembled histologically the lesions induced by transgenic expression of mutant Kras
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human cancers. It is accepted that PDAC often develops from precursor lesions termed pancreatic intraepithelial neoplasia The cellular origins of PanIN lesions and PDAC remain controversial, with different studies in murine models implicating duct cells, centroacinar cells, acinar cells undergoing acinar-to-ductal metaplasia (ADM), and even islet cells as the cell of origin [2,3,4,5,6]. Oncogenic mutations in KRAS are found in more than 95% of PDACs and appear to drive the formation of PanIN. Authors' Affiliations: Departments of 1Biochemistry and Molecular Biology and 2Developmental Biology & Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School; 3Department of Surgery, Hadassah-Hebrew University Medical Center; 4Betlehem University, Palestinian Authority, and Department of Pathology and Laboratory Medicine, Augusta Victoria Hospital, Jerusalem, Israel; and 5The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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