Dawn E. Quelle
The University of Iowa, Carver College of Medicine, USA
Title: RABL6A, a novel oncogene required for Akt-mTOR and Myc signaling in pancreatic neuroendocrine tumor cells
Biography
Biography: Dawn E. Quelle
Abstract
A better molecular understanding of pancreatic neuroendocrine tumors (PNETs) is needed to improve patient diagnosis and treatment. The PI3K/Akt/mTOR pathway is aberrantly activated in PNETs resulting in everolimus (mTOR inhibitor)-based therapies. However, sustained mTOR inhibition has the unintended consequence of hyper-activating Akt, thereby promoting drug resistance. Our data suggests that RABL6A, a novel oncoprotein amplified in PNETs, is a key regulator of this clinically relevant pathway. We found that RABL6A is essential for PNET cell proliferation and survival, and its loss dramatically reduces both Akt1 and Myc expression and activity. Given the central role of Akt1 and Myc in promoting tumorigenesis, we hypothesized that reinstating their activity would rescue the arrest phenotype caused by RABL6A loss. Individual restoration of Akt1 or c-Myc in RABL6A-depleted PNET cells partially rescued the G1 phase arrest and induced S phase entry. This coincided with decreased expression of the cell cycle inhibitor, p27Kip1, and increased levels of CKS1B, a Myc transcriptional target that promotes p27 degradation. Notably, neither Akt nor Myc activation was sufficient to restore proliferation in the absence of RABL6A since cells became arrested in S-G2/M or died via apoptosis. Thus, RABL6A controls multiple pathways essential for PNET cell cycle progression and survival. We are currently testing if RABL6A status in PNETs predicts responsiveness to clinical inhibitors of Akt, mTOR and Myc. These studies identify RABL6A as a new essential regulator of Akt1-mTOR and Myc signaling pathways, providing compelling mechanistic insight into the oncogenic function of RABL6A in PNETs
