MCM2-7 Complex is a Novel Druggable Target for Neuroendocrine Prostate Cancer

Overview

Journal Sci Rep

Specialty Science

Date 2021 Jun 26

PMID 34172788

Citations 17

Authors

En-Chi Hsu

Michelle Shen

Merve Aslan

Shiqin Liu

Manoj Kumar

Fernando Garcia-Marques

Holly M Nguyen

Rosalie Nolley

Sharon J Pitteri

Eva Corey

James D Brooks

Tanya Stoyanova

Affiliations

Soon will be listed here.

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

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