Ilknur Bugan1, Selma Kucuk1, Zeynep Karagoz1, Scott P Fraser2, Handan Kaya3, Andrew Dodson4, Christopher S Foster5, Seyhan Altun1, Mustafa B A Djamgoz6,7. 1. Department of Biology, Faculty of Science, Istanbul University, Vezneciler, Istanbul, 34134, Turkey. 2. Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. 3. Marmara University School of Medicine, Department of Pathology, Pendik, Istanbul, Turkey. 4. Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK. 5. Cellular Pathology Laboratories, HCA Healthcare UK, GPS House, 215 Great Portland Street, London, W1W 5PN, UK. 6. Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. m.djamgoz@imperial.ac.uk. 7. Cyprus International University, Biotechnology Research Centre, Haspolat, Mersin10, North Cyprus, Turkey. m.djamgoz@imperial.ac.uk.
Abstract
BACKGROUND: Voltage-gated Na+ channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo. METHODS: Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in 'normal' vs. PCa tissues. RESULTS: Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues. CONCLUSIONS: The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as anti-metastatic agents.
BACKGROUND: Voltage-gated Na+ channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo. METHODS: Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in 'normal' vs. PCa tissues. RESULTS: Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues. CONCLUSIONS: The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as anti-metastatic agents.
Authors: Jeff Holzbeierlein; Priti Lal; Eva LaTulippe; Alex Smith; Jaya Satagopan; Liying Zhang; Charles Ryan; Steve Smith; Howard Scher; Peter Scardino; Victor Reuter; William L Gerald Journal: Am J Pathol Date: 2004-01 Impact factor: 4.307
Authors: Osbaldo Lopez-Charcas; Piyasuda Pukkanasut; Sadanandan E Velu; William J Brackenbury; Tim G Hales; Pierre Besson; Juan Carlos Gomora; Sébastien Roger Journal: iScience Date: 2021-03-06