Year: 2018
Type: article
Abstract: Endogenous sphingolipids (ceramide) and related synthetic molecules (FTY720, SH-BC-893) reduce nutrient access by decreasing cell surface expression of a subset of nutrient transporter proteins. Here, we report that these sphingolipids disrupt endocytic recycling by inactivating the small GTPase ARF6. Consistent with reported roles for ARF6 in maintaining the tubular recycling endosome, MICAL-L1-positive tubules were lost from sphingolipid-treated cells. We propose that ARF6 inactivation may occur downstream of PP2A activation since: (1) sphingolipids that fail to activate PP2A did not reduce ARF6-GTP levels; (2) a structurally unrelated PP2A activator disrupted tubular recycling endosome morphology and transporter localization; and (3) overexpression of a phosphomimetic mutant of the ARF6 GEF GRP1 prevented nutrient transporter loss. ARF6 inhibition alone was not toxic; however, the ARF6 inhibitors SecinH3 and NAV2729 dramatically enhanced the killing of cancer cells by SH-BC-893 without increasing toxicity to peripheral blood mononuclear cells, suggesting that ARF6 inactivation contributes to the anti-neoplastic actions of sphingolipids. Taken together, these studies provide mechanistic insight into how ceramide and sphingolipid-like molecules limit nutrient access and suppress tumor cell growth and survival.
Source: Journal of Cell Science
DOI: 10.1242/jcs.213314
Institution: University of California, Irvine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: A Novel Approach to Prostate Cancer Therapy: Starving Tumor Cells to Death, G2447102942, G2662423001, Institute for Clinical and Translational Science, G4668025402, G5991371171, Using Sphingolipids to Target Metabolism and Metastasis in Breast Cancer, G8756261631, G9000096522, G9000258386, Cancer Center Support Grant, A Training Program for Interdisciplinary Cancer Research
OpenAlex ID: W2806223335