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

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

  • Cancer Metab. 2022 Dec 6;10(1):22. doi: 10.1186/s40170-022-00299-4.
Yao Shen # 1,  Pan Zhao # 1,  Kewei Dong # 1,  Jiajia Wang 1,  Huichen Li 1,  Mengyang Li 2,  Ruikai Li 3,  Suning Chen 4,  Yuxia Shen 1,  Zhiyu Liu 5,  Mianjiao Xie 6,  Peng Shen 7,  Jian Zhang 8
Affiliations

Affiliations

  • 1 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.
  • 2 The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
  • 3 Department of Gastrointestinal Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
  • 4 Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
  • 5 The State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
  • 6 Department of Experimental Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
  • 7 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. shenbo20110311@163.com.
  • 8 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China. biozhangj@fmmu.edu.cn.
  • # Contributed equally.
PMID: 36474242 DOI: 10.1186/s40170-022-00299-4
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.

Keywords

5-FU; Colorectal cancer; PRMT5; Tadalafil.

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