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, Gary E. Gallick

Research output: Contribution to journalArticle

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)29161-29177
Number of pages17
JournalOncotarget
Volume6
Issue number30
DOIs
StatePublished - 2015

Keywords

  • Apoptosis
  • Autophagy
  • Bone metastasis
  • MiR-34a
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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