Tadalafil increases the antitumor activity of 5-FU through inhibiting PRMT5-mediated glycolysis and cell proliferation in colorectal cancer

Abstract

Background Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood. Methods We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified. Results PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo. Conclusions Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.

5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

“…For instance, Olaparib-resistant ovarian adenocarcinoma cells and 5-FU resistant gastric cancer tissue both showed an increase in EHMT2 protein expression [ 39 , 40 ]. In addition, PRMT5 was found to be implicated in 5-FU resistance in CRC cells (HCT-116 and SW480 cell lines) in vitro and in vivo [ 41 ]. One exception in our results was found in one of the biological repeats of the 5-FU desensitized Caco-2 cells.…”

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

“…PRMT5 plays a crucial role in intestinal diseases such as enteritis and colorectal cancer development (Hernandez et al, 2023;Yang and Bedford, 2013). Mechanistic studies have suggested that PRMT5 can promote colorectal cancer cell growth by transcriptionally silencing anti-oncogenes or/and activating oncogenes (Cho et al, 2012;Prabhu et al, 2015;Shen et al, 2022;Yan et al, 2021;Zhang et al, 2015). In IBD, upregulation of PRMT5 contributes to clearing Citrobacter rodentium infection and promoting mucosal damage recovery during enteric infection (Hernandez et al, 2023).…”