Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells

• Published in: Oncotarget Vol. 6; no. 39; pp. 41535 - 41549
• Main Authors: Dykstra, Kaitlyn M, Allen, Cheryl, Born, Ella J, Tong, Huaxiang, Holstein, Sarah A
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 08.12.2015
• Subjects: Antibodies, Monoclonal - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Autophagy - drug effects; Biosynthetic Pathways - drug effects; Cell Line, Tumor; Dose-Response Relationship, Drug; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzyme Inhibitors - pharmacology; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Humans; Immunoglobulin Light Chains - metabolism; Microtubule-Associated Proteins - metabolism; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Protein Prenylation - drug effects; Protein Transport; rab GTP-Binding Proteins - metabolism; Research paper: Autophagy and Cell Death; Terpenes - metabolism; Transferases - antagonists & inhibitors; Transferases - metabolism; prenylation; autophagy; myeloma; RabGTPase; isoprenoid
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6365

Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents.