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

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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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Abbreviations

CM:

Conditioned medium

HGF:

Hepatocyte growth factor

HIF1α:

Hypoxia-inducible factor 1-alpha

MSC:

Mesenchymal stromal cells

PDGF:

Platelet-derived growth factor

PKC:

Protein kinase C

PKCζ:

Protein kinase C zeta

TADC:

Tumor-associated dendritic cells

TAM:

Tumor-associated macrophage

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Acknowledgements

We are thankful to the Director, Bose Institute (Kolkata, India), for his cooperation during the study. We thank members of the Central Instrument Facility for their assistance and Mr. Prabal Gupta for technical support.

Funding

The work was supported by the funds from the Council of Scientific and Industrial Research (CSIR), India [Grant no. 09/015(0475)2015-EMR-1].

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Authors and Affiliations

  1. Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India

    Sweta Ghosh, Subir Kumar Juin, Suchandra Bhattacharyya Majumdar, Parames C. Sil & Subrata Majumdar

  2. Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India

    Partha Nandi, Anamika Bose & Rathindranath Baral

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  1. Sweta Ghosh
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Contributions

SG designed and performed the experiments, analyzed the data, and wrote the paper; SKJ performed the experiments and analyzed the data; PN performed few experiments; SBM, AB, RNB, and PCS helped in performing some of the experiments; SM designed the project, analyzed the data, and wrote the paper.

Corresponding author

Correspondence to Subrata Majumdar.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All experiments involving animals in this study were carried out in strict accordance with guidelines established by the Institutional Animal Ethical Committee (IAEC), Bose Institute, Kolkata, India. All the experimental plan of work consisting of animals was approved by IAEC, Bose Institute and CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals), Govt. of India (Reg. no. 1796/GO/EReBiBt/S/14/CPCSEA; Approval no. IAEC/BI/18/2015).

Animal source

Female C57BL/6 mice were procured from the Central Animal House and Research Facility of Bose Institute (Kolkata, India).

Cell line authentication

B16F10 murine melanoma cells, A375 human melanoma cells, RAW264.7 murine macrophages, and THP1-derived macrophages, a non-adherent human monocyte, were procured from the National Centre for Cell Sciences, (Pune, India). The cell lines were authenticated by the vendor and the cells were used as provided by the vendor.

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Ghosh, S., Juin, S.K., Nandi, P. et al. PKCζ mediated anti-proliferative effect of C2 ceramide on neutralization of the tumor microenvironment and melanoma regression. Cancer Immunol Immunother 69, 611–627 (2020). https://doi.org/10.1007/s00262-020-02492-0

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