Oncotarget

Research Papers: Autophagy and Cell Death:

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

Kaitlyn M. Dykstra, Cheryl Allen, Ella J. Born, Huaxiang Tong and Sarah A. Holstein _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:41535-41549. https://doi.org/10.18632/oncotarget.6365

Metrics: PDF 2081 views  |   HTML 2880 views  |   ?  


Abstract

Kaitlyn M. Dykstra1, Cheryl Allen1, Ella J. Born2, Huaxiang Tong3 and Sarah A. Holstein1,4

1 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

2 Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

3 Penn State Hershey Cancer Institute, Hershey, PA, USA

4 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

Correspondence to:

Sarah A. Holstein, email:

Keywords: myeloma, RabGTPase, autophagy, prenylation, isoprenoid

Received: July 15, 2015 Accepted: November 16, 2015 Published: November 22, 2015

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6365