Reducing protein regulator of cytokinesis 1 as a prospective therapy for hepatocellular carcinoma

Xinran Liu,Kun Huang,Sheng Sun,Yangkai Li,Hong Chen,Xin-Yuan Liu,Yu Zhang,Chengyu Liu,Ling Zheng,Anlin Peng,Yuchen Chen,Lijing Meng,Xiaoping Miao

doi:10.1038/s41419-018-0555-4

Abstract

Proteins that bind to microtubule are important for cell cycle, and some of these proteins show oncogenic characteristics with mechanisms not fully understood. Herein we demonstrate overexpression of protein regulator of cytokinesis 1 (PRC1), a microtubule-associated regulator of mitosis, in human hepatocellular carcinoma (HCC). Moreover, upregulated PRC1 is associated with lower survival rates of HCC patients. Mechanistically, reducing PRC1 blocks mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent manner, and acts synergistically with microtubule-associated agents (MTAs) to suppress p53-wt or p53-null HCC cells in a p53- or p14ARF-dependent manner; while overexpressing PRC1 increases the resistance of HCC to taxol. A combined treatment of taxol/shPRC1 results in 90% suppression of tumor growth in subcutaneous HCC xenograft models. In orthotopic xenograft mice, reducing PRC1 significantly alleviates HCC development and hepatic injury. Together, our results suggest a dual-mitotic suppression approach against HCC by combining MTAs with cytokinesis inhibition, which blocks mitosis at both metaphase and telophase.

Highlights

Hepatocellular carcinoma (HCC) results in approximately 600,000 deaths worldwide annually[1]
spindle assembly checkpoint (SAC) activation is critical for Microtubuletargeting agents (MTAs) to suppress mitosis, whereas drug-resistant cancer cells can exit mitosis by prematurely entering anaphase to evade SAC (Fig. 6c)
Reducing Protein regulator of cytokinesis 1 (PRC1), which blocks cytokinesis at telophase, may target the cells escaping from the metaphase arrest bringing synergistic antitumor effects to MTAs treatment (Fig. 6c)

Summary

Introduction

Hepatocellular carcinoma (HCC) results in approximately 600,000 deaths worldwide annually[1]. Microtubuletargeting agents (MTAs), such as taxanes and epothilones, bind with microtubules, altering their dynamics, triggering the spindle assembly checkpoint (SAC) and preventing cells from entering anaphase, which causes mitotic arrest[2]. Because of drug resistance or insensitivity, applications of these chemotherapeutic agents are limited for HCC treatment[3]. During MTAs induced mitotic arrest, cancer cells either die or exit mitosis by slipping into G1 phase with mis-segregated chromosomes, displaying increased. Most strategies block mitotic exit at the metaphase-to-anaphase transition via SAC9; reduced SAC activity in cancer cells is commonly found[10], new approaches against MTA-resistant cancers are needed. Protein regulator of cytokinesis 1 (PRC1) is a microtubule binding protein required for the completion of cytokinesis at telophase[11].

Methods

Results

Conclusion