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Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation

SIMPLE SUMMARY: Recent advances in our understanding of the immune response to tumors highlighted the importance of immunogenic cell death (ICD) as a novel therapeutic strategy. This study aims to elucidate the role(s) of sphingolipids in the colorectal cancer cell (CRC) response to ICD-inducing age...

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Autores principales: Hengst, Jeremy A., Nduwumwami, Asvelt J., Yun, Jong K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657779/
https://www.ncbi.nlm.nih.gov/pubmed/36358599
http://dx.doi.org/10.3390/cancers14215182
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author Hengst, Jeremy A.
Nduwumwami, Asvelt J.
Yun, Jong K.
author_facet Hengst, Jeremy A.
Nduwumwami, Asvelt J.
Yun, Jong K.
author_sort Hengst, Jeremy A.
collection PubMed
description SIMPLE SUMMARY: Recent advances in our understanding of the immune response to tumors highlighted the importance of immunogenic cell death (ICD) as a novel therapeutic strategy. This study aims to elucidate the role(s) of sphingolipids in the colorectal cancer cell (CRC) response to ICD-inducing agents and demonstrates that sphingolipids are key regulators of ICD. Our findings provide insights into the cellular signaling mechanism of ICD that will lead to the development of improved therapeutic strategies that harness the power of the sphingolipids in the fight against CRC. ABSTRACT: We recently identified the sphingosine kinases (SphK1/2) as key intracellular regulators of immunogenic cell death (ICD) in colorectal cancer (CRC) cells. To better understand the mechanism by which SphK inhibition enhances ICD, we focused on the intracellular signaling pathways leading to cell surface exposure of calreticulin (ectoCRT). Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-X(L) and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. Inhibition of SphK1 significantly enhanced ABT/AZD-induced ectoCRT production, in a caspase 8-dependent manner. Mechanistically, we demonstrate that ABT/AZD-induced Bak/Bax activation stimulates pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling, which attenuates ectoCRT production. Additionally, we identified a regulatory role for ceramide synthase 6 (CerS6)/C16:0 ceramide in transporting of ectoCRT to the cell surface. Together, these results indicate that the sphingolipid metabolic regulators of the sphingolipid rheostat, S1P and C16:0 ceramide, influence survival/death decisions of CRC cells in response to ICD-inducing chemotherapeutic agents. Importantly, SphK1, which produces S1P, is a stress-responsive pro-survival lipid kinase that suppresses ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents.
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spelling pubmed-96577792022-11-15 Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation Hengst, Jeremy A. Nduwumwami, Asvelt J. Yun, Jong K. Cancers (Basel) Article SIMPLE SUMMARY: Recent advances in our understanding of the immune response to tumors highlighted the importance of immunogenic cell death (ICD) as a novel therapeutic strategy. This study aims to elucidate the role(s) of sphingolipids in the colorectal cancer cell (CRC) response to ICD-inducing agents and demonstrates that sphingolipids are key regulators of ICD. Our findings provide insights into the cellular signaling mechanism of ICD that will lead to the development of improved therapeutic strategies that harness the power of the sphingolipids in the fight against CRC. ABSTRACT: We recently identified the sphingosine kinases (SphK1/2) as key intracellular regulators of immunogenic cell death (ICD) in colorectal cancer (CRC) cells. To better understand the mechanism by which SphK inhibition enhances ICD, we focused on the intracellular signaling pathways leading to cell surface exposure of calreticulin (ectoCRT). Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-X(L) and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. Inhibition of SphK1 significantly enhanced ABT/AZD-induced ectoCRT production, in a caspase 8-dependent manner. Mechanistically, we demonstrate that ABT/AZD-induced Bak/Bax activation stimulates pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling, which attenuates ectoCRT production. Additionally, we identified a regulatory role for ceramide synthase 6 (CerS6)/C16:0 ceramide in transporting of ectoCRT to the cell surface. Together, these results indicate that the sphingolipid metabolic regulators of the sphingolipid rheostat, S1P and C16:0 ceramide, influence survival/death decisions of CRC cells in response to ICD-inducing chemotherapeutic agents. Importantly, SphK1, which produces S1P, is a stress-responsive pro-survival lipid kinase that suppresses ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents. MDPI 2022-10-22 /pmc/articles/PMC9657779/ /pubmed/36358599 http://dx.doi.org/10.3390/cancers14215182 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hengst, Jeremy A.
Nduwumwami, Asvelt J.
Yun, Jong K.
Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title_full Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title_fullStr Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title_full_unstemmed Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title_short Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation
title_sort regulatory role of sphingosine-1-phosphate and c16:0 ceramide, in immunogenic cell death of colon cancer cells induced by bak/bax-activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657779/
https://www.ncbi.nlm.nih.gov/pubmed/36358599
http://dx.doi.org/10.3390/cancers14215182
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