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

Autor: Hengst JA; Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA., Nduwumwami AJ; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Houston, TX 77030, USA., Yun JK; Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Oct 22; Vol. 14 (21). Date of Electronic Publication: 2022 Oct 22.
DOI: 10.3390/cancers14215182
Abstrakt: 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.
Databáze: MEDLINE
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