KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Autor:	Tinsley SL; Purdue University Interdisciplinary Life Sciences Program (PULSe), Purdue University, West Lafayette, IN, USA.; Department of Biological Sciences, Purdue University, West Lafayette, IN USA., Shelley RA; Department of Biological Sciences, Purdue University, West Lafayette, IN USA., Mall GK; Department of Biological Sciences, Purdue University, West Lafayette, IN USA., Chianis ERD; Department of Biological Sciences, Purdue University, West Lafayette, IN USA., Dhiman A; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA., Baral G; Department of Biological Sciences, Purdue University, West Lafayette, IN USA., Kothandaraman H; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA., Thoma MC; Department of Molecular Medicine and Genetics, Oregon Health and Sciences University, Portland, Oregon, USA., Daniel CJ; Department of Molecular Medicine and Genetics, Oregon Health and Sciences University, Portland, Oregon, USA., Lanman NA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA., di Magliano MP; University of Michigan School of Medicine, University of Michigan, Ann Arbor, Michigan, USA., Narla G; University of Michigan School of Medicine, University of Michigan, Ann Arbor, Michigan, USA., Solorio L; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA., Dykhuizen EC; Purdue University Interdisciplinary Life Sciences Program (PULSe), Purdue University, West Lafayette, IN, USA.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Sears RC; Department of Molecular Medicine and Genetics, Oregon Health and Sciences University, Portland, Oregon, USA.; Brenden-Colson Center for Pancreatic Care, Oregon Health and Sciences University, Portland, Oregon, USA., Allen-Petersen BL; Purdue University Interdisciplinary Life Sciences Program (PULSe), Purdue University, West Lafayette, IN, USA.; Department of Biological Sciences, Purdue University, West Lafayette, IN USA.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 23. Date of Electronic Publication: 2024 May 23.
DOI:	10.1101/2023.07.01.547283
Abstrakt:	Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRAS G12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRAS G12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo , knockout of B56α promoted KRAS G12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis. Competing Interests: Conflict of interest: G.N. receives research support from RAPPTA Therapeutics, and has an equity interest and receives consulting fees from RAPPTA Therapeutics. R.C.S serves on the scientific advisory board for RAPPTA and Larkspur, and receives sponsored research support from Cardiff Oncology and AstraZeneca. All other authors have no potential conflicts of interest.
Databáze:	MEDLINE
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