RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth
Shaikamjad Umesalma, … , Frederick W. Quelle, Dawn E. Quelle
Shaikamjad Umesalma, … , Frederick W. Quelle, Dawn E. Quelle
Published February 5, 2019
Citation Information: J Clin Invest. 2019;129(4):1641-1653. https://doi.org/10.1172/JCI123049.
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Research Article Cell biology Oncology

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

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 was the result of 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. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an 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.

Authors

Shaikamjad Umesalma, Courtney A. Kaemmer, Jordan L. Kohlmeyer, Blake Letney, Angela M. Schab, Jacqueline A. Reilly, Ryan M. Sheehy, Jussara Hagen, Nitija Tiwari, Fenghuang Zhan, Mariah R. Leidinger, Thomas M. O’Dorisio, Joseph Dillon, Ronald A. Merrill, David K. Meyerholz, Abbey L. Perl, Bart J. Brown, Terry A. Braun, Aaron T. Scott, Timothy Ginader, Agshin F. Taghiyev, Gideon K. Zamba, James R. Howe, Stefan Strack, Andrew M. Bellizzi, Goutham Narla, Benjamin W. Darbro, Frederick W. Quelle, Dawn E. Quelle

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Figure 6

RABL6A oncogenic signaling in PNETs.

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RABL6A oncogenic signaling in PNETs. Schematic showing that RABL6A inhib...
Schematic showing that RABL6A inhibits the PP2A tumor suppressor, thereby activating AKT-mTOR signaling to drive PNET proliferation and survival. In turn, PP2A can inhibit expression of RABL6A, possibly via dephosphorylation and destabilization of the protein. Earlier work showed that RABL6A can promote PNET pathogenesis by inhibiting RB1, which was associated with downregulation of CDK inhibitors (p21 and p27) and increased RB1 phosphorylation (23). PP2A-mediated dephosphorylation of p27 and RB1 increases their activities, representing additional mechanisms by which PP2A may antagonize RABL6A. Although not shown, AKT also inhibits RB1 signaling through several mechanisms. The pathways depicted here, as well as drug response assays performed in this study, predict that high RABL6A expression in patient PNETs will sensitize tumors to clinically relevant drugs that inhibit CDKs (Palbociclib), activate PP2A (SMAP), inhibit AKT (MK-2206), and inhibit mTORC1 (Everolimus). Arrows, activating events. Perpendicular bars, inhibitory events.