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Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting

Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple ca...

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Autores principales: Alshaker, Heba, Wang, Qi, Brewer, Daniel, Pchejetski, Dmitri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445839/
https://www.ncbi.nlm.nih.gov/pubmed/30971929
http://dx.doi.org/10.3389/fphar.2019.00303
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author Alshaker, Heba
Wang, Qi
Brewer, Daniel
Pchejetski, Dmitri
author_facet Alshaker, Heba
Wang, Qi
Brewer, Daniel
Pchejetski, Dmitri
author_sort Alshaker, Heba
collection PubMed
description Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways.
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spelling pubmed-64458392019-04-10 Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting Alshaker, Heba Wang, Qi Brewer, Daniel Pchejetski, Dmitri Front Pharmacol Pharmacology Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways. Frontiers Media S.A. 2019-03-27 /pmc/articles/PMC6445839/ /pubmed/30971929 http://dx.doi.org/10.3389/fphar.2019.00303 Text en Copyright © 2019 Alshaker, Wang, Brewer and Pchejetski. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Alshaker, Heba
Wang, Qi
Brewer, Daniel
Pchejetski, Dmitri
Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title_full Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title_fullStr Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title_full_unstemmed Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title_short Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting
title_sort transcriptome-wide effects of sphingosine kinases knockdown in metastatic prostate and breast cancer cells: implications for therapeutic targeting
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445839/
https://www.ncbi.nlm.nih.gov/pubmed/30971929
http://dx.doi.org/10.3389/fphar.2019.00303
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