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

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.

Inhibition of kinesin family member 20B sensitizes hepatocellular carcinoma cell to microtubule‐targeting agents by blocking cytokinesis

“…Nuclei and microtubule staining were carried out as previously reported . Cells were seeded on glass coverslips, and 24 hours later they were infected with adenovirus at MOI of 1.…”

“…Nuclei and microtubule staining were carried out as previously reported. 24 Cells were seeded on glass coverslips, and 24 hours later they were infected with adenovirus at MOI of 1. Cells were then fixed with 4% paraformaldehyde, and costained with Phalloidin Alexa Fluor 555 (Molecular Probes, Eugene, OR, USA) and DAPI (Sigma-Aldrich).…”

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

“…Conversely, as unfavorable factors for HCC prognosis, the upregulated expression of molecules can directly promote hepatoma cell growth and indirectly facilitate HCC development by inducing chemotherapy resistance, all of which are mainly associated with decreased p53 activation. Protein regulator of cytokinesis 1 (PRC1) can promote cytokinesis of HCC cells and induce HCC cell desensitization to taxol by inhibiting p53/p21 or p53/ p14ARF activation 163 ; SIRT7 can cause doxorubicin resistance by interacting and inducing deacetylation of p53, and thereby reducing affinity for the NOXA promoter and its transcription 164 . In addition, protein myosin light chain 6B (MYL6B) can promote HCC development by binding MDM2 and p53 proteins, accelerating the p53 degradation 165 .…”

Mechanisms of the Ase1/PRC1/MAP65 family in central spindle assembly

“…The overexpression of PRC1 can lead to cytokinesis failure and chromosomal instability, further stimulating aneuploidy and tumorigenesis. High expression of PRC1 is closely associated with several phenotypes in diverse tumours: poor differentiation, large tumour size and high clinical grade in oral squamous cell carcinomas (Wu et al, ), lymph node metastasis and poor prognosis in lung adenocarcinoma patients (Zhan et al, ), the early recurrence of hepatocellular carcinoma (Chen et al, ), chemoresistance to 5‐florouracil and Taxol, and lower survival rate of hepatocellular carcinoma patients (Wang et al, ; Liu et al, ) (Table ).…”

“…PRC1 ablation leads to G2/M phase arrest in lung adenocarcinoma (Zhan et al, ) and oral squamous cell carcinomas (Wu et al, ), but the mechanism remains unclear. PRC1 also blocks mitotic exit of hepatocellular carcinoma cells at telophase in a spindle assembly checkpoint‐independent manner involving a tumor‐suppressor p53‐dependent pathway (Liu et al, ). p53 is a G1/S and G2/M checkpoint protein, which inhibits PRC1 expression, and the p53/PRC1/EGFR signalling pathway controls cell proliferation and the cell cycle (Li, Lin, & Liu, ; Wu et al, ).…”