Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

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Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

10.1101/2020.09.11.293035 ◽

2020 ◽

Cited By ~ 1

Author(s):

Fei Li ◽

Ming Han ◽

Pengfei Dai ◽

Wei Xu ◽

Juan He ◽

...

Keyword(s):

Prostate Cancer ◽

Lung Cancer ◽

Cancer Cells ◽

Human Lung ◽

Host Cells ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Lung Cells ◽

Prostate Cancer Cells ◽

Human Lung Cells

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a relatively new antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cancer cells (LNCaP) but not in human lung cancer cells or patient-derived lung organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, enzalutamide showed no antiviral activity due to the AR independence of TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19.

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Distinct roles for the RNA-binding protein Staufen1 in prostate cancer

BMC Cancer ◽

10.1186/s12885-021-07844-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kristen A. Marcellus ◽

Tara E. Crawford Parks ◽

Shekoufeh Almasi ◽

Bernard J. Jasmin

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Rna Binding ◽

Prostate Cancer Cell ◽

Rna Binding Protein ◽

Migration And Invasion ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Prostate Cells

Abstract Background Prostate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer. Methods Using a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated. Results We show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase. Conclusions Collectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.

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AS1 expression in prostate cancer and its effects on proliferation and invasion of prostate cancer cells

Cancer Biomarkers ◽

10.3233/cbm-203021 ◽

2021 ◽

pp. 1-9

Author(s):

Yuxin Li ◽

Xiaohong Zhuang ◽

Li Zhuang ◽

Hongjian Liu

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Related Protein ◽

Prostate Cancer Cells ◽

Blank Group ◽

Normal Prostate ◽

Cell Cycles ◽

Prostate Cells ◽

Proliferation And Invasion

This paper aimed at investigating AS1 expression in prostate cancer (PCa) and its effects on the proliferation and invasion of prostate cancer cells (PCCs). The prostate tissues and the matched adjacent normal prostate tissues excised and preserved during radical prostatectomy in our hospital were collected. The LncRNA NCK1-AS1 expression was detected. PCa patients were followed up for three years to analyze their prognosis. The correlation of LncRNA NCK1-AS1 expression with clinicopathological features was analyzed. Human normal prostate cells and human PCCs were selected, in which LncRNA NCK1-AS1 expression was tested to screen and then transfect the cells. Cell proliferation, invasion and migration were detected. Cell cycles and apoptosis were analyzed. Compared with the adjacent normal tissues, LncRNA NCK1-AS1 was highly expressed in the prostate cancer tissues. Its expression was remarkably different in those with different stages of TNM and with lymphatic metastasis or not. The prognosis of patients with high LncRNA NCK1-AS1 expression was remarkably poorer than that of those with low expression. Compared with the human normal prostate cells, LncRNA NCK1-AS1 expression in the human PCCs remarkably rose, with the greatest difference in 22Rv1 cells. Compared with the Blank group, cell proliferation and the number of plate cloned cells remarkably reduced in the sh-NCK1-AS1 group. Additionally, in this group, the number of invasive and migratory cells remarkably reduced; the expression of invasion-related protein E-cadherin remarkably rose but that of MMP-2 remarkably reduced; cell cycles were arrested and the expression of cycle-related proteins (CDK4, CDK6, cyclin D1) remarkably reduced; the apoptotic rate and the expression of apoptosis-related protein Bax remarkably rose. LncRNA NCK1-AS1 is highly expressed in PCa, so its down-regulation can inhibit PCCs from proliferating and reduce the number of invasive cells.

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Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Cancers ◽

10.3390/cancers13071727 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1727

Author(s):

Ana Carolina B. Sant’Anna-Silva ◽

Juan A. Perez-Valencia ◽

Marco Sciacovelli ◽

Claude Lalou ◽

Saharnaz Sarlak ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Carbon Metabolism ◽

Disease Free Survival ◽

Building Blocks ◽

Malignant Cells ◽

Mitochondrial Complex ◽

Prostate Cancer Cells ◽

Prostate Cells ◽

Malignant Prostate

Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.

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Rosa canina Extract has Antiproliferative and Proapoptotic Effects on Human Lung and Prostate Cancer Cells

Nutrition and Cancer ◽

10.1080/01635581.2019.1625936 ◽

2019 ◽

Vol 72 (2) ◽

pp. 273-282 ◽

Cited By ~ 8

Author(s):

Kagan Kilinc ◽

Selim Demir ◽

Ibrahim Turan ◽

Ahmet Mentese ◽

Asim Orem ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Human Lung ◽

Prostate Cancer Cells ◽

Rosa Canina

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TGF-β Effects on Prostate Cancer Cell Migration and Invasion Are Mediated by PGE2 through Activation of PI3K/AKT/mTOR Pathway

Endocrinology ◽

10.1210/en.2012-2074 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1768-1779 ◽

Cited By ~ 111

Author(s):

BaoHan T. Vo ◽

Derrick Morton ◽

Shravan Komaragiri ◽

Ana C. Millena ◽

Chelesie Leath ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Mammalian Target Of Rapamycin ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

Protein Levels ◽

Prostate Cells ◽

Pc3 Cells ◽

Cox 2

Abstract TGF-β plays an important role in the progression of prostate cancer. It exhibits both tumor suppressor and tumor-promoting activities. Correlations between cyclooxygenase (COX)-2 overexpression and enhanced production of prostaglandin (PG)E2 have been implicated in cancer progression; however, there are no studies indicating that TGF-β effects in prostate cancer cells involve PGE2 synthesis. In this study, we investigated TGF-β regulation of COX-1 and COX-2 expression in prostate cancer cells and whether the effects of TGF-β on cell proliferation and migration are mediated by PGE2. COX-1 protein was ubiquitously expressed in prostate cells; however, COX-2 protein levels were detected only in prostate cancer cells. TGF-β treatment increased COX-2 protein levels and PGE2 secretion in PC3 cells. Exogenous PGE2 and PGF2α had no effects on cell proliferation in LNCaP, DU145, and PC3 cells whereas PGE2 and TGF-β induced migration and invasive behavior in PC3 cells. Only EP2 and EP4 receptors were detected at mRNA levels in prostate cells. The EP4-targeting small interfering RNA inhibited PGE2 and TGF-β-induced migration of PC3 cells. TGF-β and PGE2 induce activation of PI3K/AKT/mammalian target of rapamycin pathway as indicated by increased AKT, p70S6K, and S6 phosphorylation. Rapamycin completely blocked the effects of TGF-β and PGE2 on phosphorylation of p70S6K and S6 but not on AKT phosphorylation. PGE2 and TGF-β induced phosphorylation of AKT, which was blocked by antagonists of PGE2 (EP4) receptors (L161982, AH23848) and PI3K inhibitor (LY294002) in PC3 cells. Pretreatment with L161982 or AH23848 blocked the stimulatory effects of PGE2 and TGF-β on cell migration, whereas LY294002 or rapamycin completely eliminated PGE2, TGF-β, and epidermal growth factor-induced migration in PC3 cells. We conclude that TGF-β increases COX-2 levels and PGE2 secretion in prostate cancer cells which, in turn, mediate TGF-β effects on cell migration and invasion through the activation of PI3K/AKT/mammalian target of rapamycin pathway.

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New copper(i) complexes selective for prostate cancer cells

Dalton Transactions ◽

10.1039/d0dt02157a ◽

2020 ◽

Vol 49 (35) ◽

pp. 12273-12286

Author(s):

João Franco Machado ◽

Diogo Sequeira ◽

Fernanda Marques ◽

M. Fátima M. Piedade ◽

Maria J. Villa de Brito ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

High Selectivity ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

New Family ◽

Prostate Cells

Synthesis of a new family of Cu(i)–phosphane complexes with N,O-heteroaromatic ligands leads to the complexes showing impressive cytotoxicity against LNCap human prostate cancer cells allied to high selectivity than against RWPE non-tumoral prostate cells.

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