Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism Underlying Tadalafil in Colorectal Cancer

Overview

Journal Front Pharmacol

Date 2022 Jun 13

PMID 35694253

Authors

Pan Zhao

Yao Shen

Mengyang Li

Hanjun Dan

Zhiming Zhao

Jian Zhang

Affiliations

Soon will be listed here.

Abstract

The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in colorectal cancer were not fully understood. In this study, we assessed the anti-tumor activity of tadalafil in human colorectal cancer cells. A systematic perspective of the tadalafil-induced anti-tumor mechanism was provided by the integration of transcriptomics and metabolomics. We found that differentially expressed genes (DEGs) were mainly involved in microRNAs in cancer, purine metabolism, glycosphingolipid biosynthesis, arginine biosynthesis, and amino acid metabolism. Amino acid metabolism, especially alanine, aspartate, and glutamate metabolism was the most of the differentially accumulated metabolites (DAMs) through the analysis of metabolomics. The conjoint analysis of DEGs and DAMs presented that they were also mainly involved in alanine, aspartate, and glutamate metabolism. Amino acid metabolism-related genes, , were significantly decreased after tadalafil treatment. In particular, the disturbance of alanine, aspartate, and glutamate metabolism may be the explanation for the major mechanism resulting from tadalafil anti-tumor activity.

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References

Delage B, Fennell D, Nicholson L, McNeish I, Lemoine N, Crook T . Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010; 126(12):2762-72. DOI: 10.1002/ijc.25202. View

Dillon B, Prieto V, Curley S, Ensor C, Holtsberg F, Bomalaski J . Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer. 2004; 100(4):826-33. DOI: 10.1002/cncr.20057. View

Roberts J, Booth L, Conley A, Cruickshanks N, Malkin M, Kukreja R . PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells. Cancer Biol Ther. 2014; 15(6):758-67. PMC: 4049791. DOI: 10.4161/cbt.28553. View

Behrenbruch C, Shembrey C, Paquet-Fifield S, Molck C, Cho H, Michael M . Surgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process. Clin Exp Metastasis. 2018; 35(4):333-345. DOI: 10.1007/s10585-018-9873-2. View

Huang W, Sundquist J, Sundquist K, Ji J . Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer. Nat Commun. 2020; 11(1):3191. PMC: 7314744. DOI: 10.1038/s41467-020-17028-4. View

Huang H, Wu W, Wang Y, Wang J, Fang F, Tsai J . ASS1 as a novel tumor suppressor gene in myxofibrosarcomas: aberrant loss via epigenetic DNA methylation confers aggressive phenotypes, negative prognostic impact, and therapeutic relevance. Clin Cancer Res. 2013; 19(11):2861-72. DOI: 10.1158/1078-0432.CCR-12-2641. View

Wang R, Chen W, Zhang Q, Liu Y, Qiao X, Meng K . Phosphodiesterase type 5 inhibitor Tadalafil increases Rituximab treatment efficacy in a mouse brain lymphoma model. J Neurooncol. 2014; 122(1):35-42. DOI: 10.1007/s11060-014-1690-0. View

Padma-Nathan H, McMurray J, Pullman W, Whitaker J, Saoud J, Ferguson K . On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res. 2001; 13(1):2-9. DOI: 10.1038/sj.ijir.3900631. View

Nappi A, Berretta M, Romano C, Tafuto S, Cassata A, Casaretti R . Metastatic Colorectal Cancer: Role of Target Therapies and Future Perspectives. Curr Cancer Drug Targets. 2017; 18(5):421-429. DOI: 10.2174/1568009617666170209095143. View

10.

Thompson W, Piazza G, Li H, Liu L, Fetter J, Zhu B . Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000; 60(13):3338-42. View

11.

Califano J, Khan Z, Noonan K, Rudraraju L, Zhang Z, Wang H . Correction: Tadalafil Augments Tumor-specific Immunity in Patients with Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2018; 24(23):6100. DOI: 10.1158/1078-0432.CCR-18-3298. View

12.

Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W . Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006; 203(12):2691-702. PMC: 2118163. DOI: 10.1084/jem.20061104. View

13.

Farshidfar F, Weljie A, Kopciuk K, Hilsden R, McGregor S, Buie W . A validated metabolomic signature for colorectal cancer: exploration of the clinical value of metabolomics. Br J Cancer. 2016; 115(7):848-57. PMC: 5046202. DOI: 10.1038/bjc.2016.243. View

14.

Peak T, Richman A, Gur S, Yafi F, Hellstrom W . The Role of PDE5 Inhibitors and the NO/cGMP Pathway in Cancer. Sex Med Rev. 2016; 4(1):74-84. DOI: 10.1016/j.sxmr.2015.10.004. View

15.

Korangath P, Teo W, Sadik H, Han L, Mori N, Huijts C . Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate. Clin Cancer Res. 2015; 21(14):3263-73. PMC: 4696069. DOI: 10.1158/1078-0432.CCR-14-1200. View

16.

Booth L, Roberts J, Poklepovic A, Gordon S, Dent P . PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide. Oncotarget. 2016; 8(1):1449-1468. PMC: 5352068. DOI: 10.18632/oncotarget.13640. View

17.

Ammirante M, Shalapour S, Kang Y, Jamieson C, Karin M . Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci U S A. 2014; 111(41):14776-81. PMC: 4205637. DOI: 10.1073/pnas.1416498111. View

18.

Jiang S, Yan W . Succinate in the cancer-immune cycle. Cancer Lett. 2017; 390:45-47. DOI: 10.1016/j.canlet.2017.01.019. View

19.

Goedert J, Sampson J, Moore S, Xiao Q, Xiong X, Hayes R . Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis. 2014; 35(9):2089-96. PMC: 4146421. DOI: 10.1093/carcin/bgu131. View

20.

Miller K, Nogueira L, Mariotto A, Rowland J, Yabroff K, Alfano C . Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019; 69(5):363-385. DOI: 10.3322/caac.21565. View