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.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the United States [1], with mortality due mainly to metastasis to the bone [2]
MiR-34a is downregulated in increasing stages of prostate cancer and in metastatic prostate cancer cell lines while its targets are overexpressed in metastatic PCa cells
To identify miRNAs that target at least seven or more genes frequently upregulated in prostate cancer relative to the normal prostate gland, we used GEO datasets and determined overlap with miRNAs that target genes upregulated in metastatic prostate cancer relative to primary cancer (GSE3325)
Summary
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the United States [1], with mortality due mainly to metastasis to the bone [2]. We used an unbiased systems-based approach to identify miRNAs that are downregulated in prostate cancer with the goal of targeting multiple gene products that are overexpressed in this disease and that promote tumor progression and bone metastasis This approach led to identifying miR-34a, a tumor suppressive miRNA that is downregulated in the advanced stages of prostate cancer. Only autophagy has been described as both pro-tumorigenic by promoting survival under nutritional or chemotherapeutic stress and tumor suppressive, by promoting cancer cell death depending on the cellular context and different inducers of autophagy [17, 23,24,25,26] These diametrically opposed biologic effects may be due, in part, to recent understanding that “canonical” and “non-canonical” autophagy pathways requiring different intermediates can elicit diverse effects in tumor cells [27, 28]. As decreased expression of the miR-34a targets, MET and Axl is associated with the induction of autophagy [29, 30], understanding the form of autophagy induced by miR-34a in prostate cancer is important for therapeutic opportunities for miR-34a replacement in bone metastatic prostate cancer
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