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

Cell Death Dis. 2018 May 1;9(5):534. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Cycle Proteins / biosynthesis*
  • Cell Cycle Proteins / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitosis / drug effects*
  • Mitosis / genetics
  • Paclitaxel / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • PRC1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Paclitaxel