A SMAP in the face for cancer

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

“…PP2A activation reduces AKT-S473 phosphorylation, downregulates RABL6A levels, and induces PNET cell death in a RABL6A-dependent manner. Recent papers published by Michael Ohlmeyer's group and us describe specific SMAPs (50,51). These tricyclic compounds were originally derived from neuroleptic drugs that were reengineered to neutralize their CNS effects, resulting in a novel class of specific PP2A-activating compounds (51,52).…”

“…This correlated with dramatic reduction in the long-term growth of BON-1 and Qgp1 cells, with essentially no colonies detected in cells exposed to 10-20 μM SMAP (Figure 4, B and C). Quantitative proliferation assays were conducted to determine the IC 50 To determine if SMAP inhibited PNET cell growth in a RAB-L6A-dependent manner, BON-1 control and RABL6A knockdown cells were treated with increasing doses of SMAP and relative cell numbers were quantified. As shown in Figure 4E, loss of RABL6A significantly reduced the cellular response to SMAP treatment.…”

“…Importantly, an orally bioavailable SMAP effectively suppressed PNET cell growth in vitro and in vivo. Pharmacological restoration of PP2A tumor suppressive phosphatase activity is an emerging strategy for cancer therapy (29,30,50), one that would deliver a new treatment option to clinicians and patients for managing advanced PNETs.…”

“…The rationale for reactivating PP2A in anticancer therapy is compelling. First and foremost, PP2A is a powerful tumor suppressor that accounts for over 50% of serine/threonine phosphatase activity in mammalian cells (31,50). As such, PP2A controls a wide diversity of substrates and exerts its antitumorigenic effects by inhibiting numerous oncogenic proteins (such as AKT, Ras, Erk, Myc, JAK2, and STAT5) and activating various tumor suppressor proteins (such as RB1, PTPN6, and GSK-3β) (29,31,40).…”

“…trol certain PP2A regulatory B subunits, particularly those (e.g., B56γ and B56β) that regulate AKT-S473 phosphorylation (40)(41)(42) and are downregulated in various cancers (29,30). Among the PP2A inhibitors, increased expression of CIP2A (cancerous inhibitor of PP2A) has been observed in a wide variety of human cancers (reviewed in 29,30,50). We found that RABL6A loss caused significant downregulation of CIP2A expression (Supplemental Figure 6, A and D), consistent with elevated PP2A activity in those cells.…”