Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer

Abstract

Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In this study, we found a positive correlation between the expression of UBE2C and PLK1/BIRC5 in the Cancer Genome Atlas (TCGA) database, revealing a potential combination therapy candidate for pan-cancer. Quantitative real-time PCR (qRT-PCR), Western blotting (WB), cell phenotype detection, and RNA-seq techniques were used to evidence the effectiveness of the combination candidate. We found that combined interference of UBE2C with PLK1 and UBE2C with BIRC5 affected metabolic pathways by significantly downregulating the mRNA expression of IDH1 and ACLY, which was related to the synthesis of acetyl-CoA. By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer.

Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data

“…Additionally, PLK1 is indispensable for re-entering mitosis following recovery from G2 phase arrest induced by DNA damage, justifying its exploration as a potential therapeutic target for cancer [54]. Our previous studies have demonstrated that inhibiting PLK1 significantly impedes the cell cycle and proliferation of liver cancer cells [55]. Volasertib, among several PLK1 inhibitors, stands out as a highly selective inhibitor of the PLK family with the most significant effect on PLK1 [56].…”

Special Issue: “Drug Repurposing for Cancer Therapies”

“…Another paper published by Keying Liang and colleagues proposed a novel combined targeted therapy for cancer patients with higher expression levels of polo-like kinase 1 (PLK1) and ATP citrate synthase (ACLY) [11]. By using RNA-seq technology, the authors verified that the combined inhibition of ubiquitin conjugating enzyme E2 C (UBE2C) and PLK1 reduced cancer cell proliferation, migration, and colony formation, while inducing cell cycle arrest and apoptosis.…”