MiR-100-5p inhibition induces apoptosis in dormant prostate cancer cells and prevents the emergence of castration-resistant prostate cancer

Noushin Nabavi,Erik Venalainen,Anne Haegert,Colin Collins,Hui Xue,Nur Ridzwan Nur Saidy,Rebecca Wu,Abhijit Parolia,Yuwei Wang,Francesco Crea,Yuzhuo Wang,Xin Dong

doi:10.1038/s41598-017-03731-8

Noushin Nabavi, Erik Venalainen + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-03731-8

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Abstract

Carcinoma of the prostate is the most common cancer in men. Treatment of aggressive prostate cancer involves a regiment of radical prostectomy, radiation therapy, chemotherapy and hormonal therapy. Despite significant improvements in the last decade, the treatment of prostate cancer remains unsatisfactory, because a significant fraction of prostate cancers develop resistance to multiple treatments and become incurable. This prompts an urgent need to investigate the molecular mechanisms underlying the evolution of therapy-induced resistance of prostate cancer either in the form of castration-resistant prostate cancer (CRPC) or transdifferentiated neuroendocrine prostate cancer (NEPC). By analyzing micro-RNA expression profiles in a set of patient-derived prostate cancer xenograft tumor lines, we identified miR-100-5p as one of the key molecular components in the initiation and evolution of androgen ablation therapy resistance in prostate cancer. In vitro results showed that miR-100-5p is required for hormone-independent survival and proliferation of prostate cancer cells post androgen ablation. In Silico target predictions revealed that miR-100-5p target genes are involved in key aspects of cancer progression, and are associated with clinical outcome. Our results suggest that mir-100-5p is a possible therapeutic target involved in prostate cancer progression and relapse post androgen ablation therapy.

Highlights

Current cancer therapeutics are often effective in treating clinically evident tumors; patient mortality is often due to the permanence of residual tumor cells (RTCs) or disseminated tumor cells (DTCs) that are highly resistant to therapy and capable of generating metastatic and incurable diseases[1]
To determine the dormant status of tumor cells, cell proliferation and apoptosis were evaluated by immunohistochemical staining for human-specific anti-Ki-67 and anti-Caspase 3 (Casp-3) antibodies, respectively, in the Cx series of Living Tumor Laboratory (LTL)-313B patient-derived xenograft (PDX)
These findings indicate that Androgen-deprivation therapy (ADT) can lead to therapy-induced dormancy and development of relapsed tumors in the prostate cancer (PCa) PDX models

Summary

Introduction

Current cancer therapeutics are often effective in treating clinically evident tumors; patient mortality is often due to the permanence of residual tumor cells (RTCs) or disseminated tumor cells (DTCs) that are highly resistant to therapy and capable of generating metastatic and incurable diseases[1]. These deadly seeds are able to remain “dormant”, escaping detection, for an extensive period of time until the emergence of a clinically evident disease. Targeting ADT-induced DCCs may be the key to preventing additional cascades of dormancy-relapse cycles and the emergence of CRPC and/or NEPC. To the best of our knowledge, miRNAs have not yet been studied in ADT-induced PCa dormancy

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