RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

J Clin Invest. 2019 Feb 05;:

Authors: Umesalma S, Kaemmer CA, Kohlmeyer JL, Letney BL, Schab AM, Reilly JA, Sheehy RM, Hagen J, Tiwari N, Zhan F, Leidinger MR, O'Dorisio TM, Dillon JS, Merrill RA, Meyerholz DK, Perl AL, Brown BJ, Braun TA, Scott AT, Ginader T, Taghiyev AF, Zamba GK, Howe JR, Strack S, Bellizzi AM, Narla G, Darbro BW, Quelle FW, Quelle DE

Abstract
Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A depleted cells resulted from increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A depleted cells whereas PP2A reactivation using a specific small molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. This work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

PMID: 30721156 [PubMed - as supplied by publisher]

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