Impact of TMPRSS2 Expression, Mutation Prognostics, and Small Molecule (CD, AD, TQ, and TQFL12) Inhibition on Pan-Cancer Tumors and Susceptibility to SARS-CoV-2

Abstract

As a cellular protease, transmembrane serine protease 2 (TMPRSS2) plays roles in various physiological and pathological processes, including cancer and viral entry, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we conducted expression, mutation, and prognostic analyses for the TMPRSS2 gene in pan-cancers as well as in COVID-19-infected lung tissues. The results indicate that TMPRSS2 expression was highest in prostate cancer. A high expression of TMPRSS2 was significantly associated with a short overall survival in breast invasive carcinoma (BRCA), sarcoma (SARC), and uveal melanoma (UVM), while a low expression of TMPRSS2 was significantly associated with a short overall survival in lung adenocarcinoma (LUAD), demonstrating TMPRSS2 roles in cancer patient susceptibility and severity. Additionally, TMPRSS2 expression in COVID-19-infected lung tissues was significantly reduced compared to healthy lung tissues, indicating that a low TMPRSS2 expression may result in COVID-19 severity and death. Importantly, TMPRSS2 mutation frequency was significantly higher in prostate adenocarcinoma (PRAD), and the mutant TMPRSS2 pan-cancer group was significantly associated with long overall, progression-free, disease-specific, and disease-free survival rates compared to the wild-type (WT) TMPRSS2 pan-cancer group, demonstrating loss of functional roles due to mutation. Cancer cell lines were treated with small molecules, including cordycepin (CD), adenosine (AD), thymoquinone (TQ), and TQFL12, to mediate TMPRSS2 expression. Notably, CD, AD, TQ, and TQFL12 inhibited TMPRSS2 expression in cancer cell lines, including the PC3 prostate cancer cell line, implying a therapeutic role for preventing COVID-19 in cancer patients. Together, these findings are the first to demonstrate that small molecules, such as CD, AD, TQ, and TQFL12, inhibit TMPRSS2 expression, providing novel therapeutic strategies for preventing COVID-19 and cancers.

Effect of DPP4/CD26 expression on SARS‑CoV‑2 susceptibility, immune response, adenosine (derivatives m62A and CD) regulations on patients with cancer and healthy individuals

“…CTSL is another receptor for SARS-CoV-2 ( 57 ). Additionally, CD suppresses the expression of other SARS-CoV-2 receptors (e.g., FURIN and transmembrane serine protease 2), in different cancer cells ( 47 , 80 ). Evidence indicates that a large number of multinucleated cells characteristic of syncytial pathology are present in patients with COVID-19 ( 73 ).…”

Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

“…CD is an adenosine analog with wide pharmacological effects and maybe resistance to a variety of tumors ( 18 , 19 , 47 ) and viruses ( 48 – 50 ), including SARS-CoV-2 ( 20 , 29 , 51 , 52 ). We analyzed the role of CD in different tumor cells and found that CD concentration-dependently decreased SOX9 protein and mRNA expression in 22RV1, PC3, and H1975, suggesting that the anticancer effect of CD may be associated with SOX9 inhibition.…”

“…All cells were cultured in a 37°C incubator with 5% CO 2 . CD was obtained from Chengdu Must Bio-Technology Co. Ltd. (Chengdu, Sichuan, China), which has been used previously ( 18 , 28 , 29 ). Cells were inoculated in 12-well plates and treated with CD at final concentrations of 0, 10, 20, and 40 µM for 24 h. Protein was collected, and expression levels were monitored by Western blot.…”

“…Cells were inoculated in 12-well plates and treated with CD at final concentrations of 0, 10, 20, and 40 µM for 24 h. Protein was collected, and expression levels were monitored by Western blot. Total RNA was extracted by reverse transcription ( 29 , 30 ).…”

Impact of BSG/CD147 gene expression on diagnostic, prognostic and therapeutic strategies towards malignant cancers and possible susceptibility to SARS-CoV-2

“…CD also showed burly binding affinities with S-protein and Mpro proteins from SARS-CoV-2 [ 46 ]. In addition, CD has been found to prevent the expressions of FURIN, TMPRSS2 and CTSL, the SARS-CoV-2 receptors, on cancer cell lines in dose dependent manners [ 34 , 47 , 48 ]. m 6 2 A, as a modified ribonucleoside [ 49 ], was also reported to inhibit the expressions of CTSL on cancer cells in dose dependent manners [ 47 ].…”