Oncotarget

Research Papers:

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

Sanchaika Gaur, Yunfei Wen, Jian H. Song, Nila U. Parikh, Lingegowda S. Mangala, Alicia M. Blessing, Cristina Ivan, Sherry Y. Wu, Andreas Varkaris, Yan Shi, Gabriel Lopez-Berestein, Daniel E. Frigo, Anil K. Sood and Gary E. Gallick _

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Oncotarget. 2015; 6:29161-29177. https://doi.org/10.18632/oncotarget.4971

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Abstract

Sanchaika Gaur1,2,9, Yunfei Wen3, Jian H. Song1, Nila U. Parikh1, Lingegowda S. Mangala3,4, Alicia M. Blessing5, Cristina Ivan3,4, Sherry Y. Wu3, Andreas Varkaris1, Yan Shi5, Gabriel Lopez-Berestein4,6, Daniel E. Frigo5,7, Anil K. Sood2,3,4,8 and Gary E. Gallick1,2

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.


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