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01-04-2020 | Melanoma | Original Article

PKCζ mediated anti-proliferative effect of C2 ceramide on neutralization of the tumor microenvironment and melanoma regression

Authors: Sweta Ghosh, Subir Kumar Juin, Partha Nandi, Suchandra Bhattacharyya Majumdar, Anamika Bose, Rathindranath Baral, Parames C. Sil, Subrata Majumdar

Published in: Cancer Immunology, Immunotherapy | Issue 4/2020

Abstract

Immunotherapy, which has advantages over chemotherapy due to lesser toxicity and higher specificity, is on the rise to treat cancer. Recently, pro-apoptotic glycolipid, ceramide has emerged as a key regulator in cancer immunotherapy. The present study elucidated the potential anti-melanoma efficacy of cell-permeable, exogenous C2 ceramide on cell death and amelioration of tumor microenvironment (TME). We, for the first time, demonstrated that C2 ceramide triggered apoptosis of melanoma cells by augmenting PKCζ along with pro-inflammatory cytokines and signaling factors. C2 ceramide showed a PKCζ-mediated tumor-suppressive role in melanoma without exhibiting hepatotoxicity and nephrotoxicity. Moreover, PKCζ was revealed as one of the key regulators of Akt and ceramide during C2 ceramide-mediated apoptosis. C2 ceramide was effective in repolarization of M2 macrophage phenotype and reduction of angiogenic factors such as VEGF, VEGFR1, VEGFR2, HIF1α. Interestingly, PKCζ knockdown attenuated C2 ceramide-mediated inhibition of melanoma progression. Restoration of the Th1 type TME by C2 ceramide enhanced cytotoxic T cell-mediated killing of melanoma cells. Altogether, the study unraveled that C2 ceramide-induced PKCζ was associated with favorable immune cell functioning in TME leading to melanoma regression. Thus, our findings explored a novel mechanistic insight into C2 ceramide as a promising immunotherapeutic agent in melanoma treatment.

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Title: PKCζ mediated anti-proliferative effect of C2 ceramide on neutralization of the tumor microenvironment and melanoma regression
Authors: Sweta Ghosh
Subir Kumar Juin
Partha Nandi
Suchandra Bhattacharyya Majumdar
Anamika Bose
Rathindranath Baral
Parames C. Sil
Subrata Majumdar
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Published in: Cancer Immunology, Immunotherapy / Issue 4/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02492-0

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