Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy

// Sanchaika Gaur 1,2,9 , Yunfei Wen 3 , Jian H. Song 1 , Nila U. Parikh 1 , Lingegowda S. Mangala 3,4 , Alicia M. Blessing 5 , Cristina Ivan 3,4 , Sherry Y. Wu 3 , Andreas Varkaris 1 , Yan Shi 5 , Gabriel Lopez-Berestein 4,6 , Daniel E. Frigo 5,7 , Anil K. Sood 2,3,4,8 and Gary E. Gallick 1,2 1 Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA 2 Program in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, TX, USA 3 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Center for Nuclear Receptors and Cell Signaling, Departments of Biology and Biochemistry, University of Houston, TX, USA 6 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Genomic Medicine Program, The Houston Methodist Research Institute, Houston, TX, USA 8 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA Correspondence: Gary E. Gallick, email: // Keywords : prostate cancer, miR-34a, bone metastasis, apoptosis, autophagy Received : April 07, 2015 Accepted : July 11, 2015 Published : July 22, 2015 Abstract While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor growth and preserved bone integrity in a xenograft model representative of established PCa bone metastasis. Expression of miR-34a induced apoptosis in PCa cells, and, in accord with downregulation of targets associated with PCa growth, including MET and Axl and c-Myc, also induced a form of non-canonical autophagy that is independent of Beclin-1, ATG4, ATG5 and ATG7. MiR-34a-induced autophagy is anti-proliferative in prostate cancer cells, as blocking apoptosis still resulted in growth inhibition of tumor cells. Thus, combined effects of autophagy and apoptosis are responsible for miR-34a-mediated prostate tumor growth inhibition, and have translational impact, as this non-canonical form of autophagy is tumor inhibitory. Together, these results provide a new understanding of the biological effects of miR-34a and highlight the clinical potential for miR-34a delivery as a treatment for bone metastatic prostate cancer.