Abstract
Ceramide is one of the important cellular components involved in cancer regulation and exerts its pleiotropic role in the protective immune response without exhibiting any adverse effects during malignant neoplasm. Although, the PKCδ-ceramide axis in cancer cells has been an effective target in reduction of cancer, involvement of PKCδ in inducing nephrotoxicity have become a major questionnaire. In the present study, we have elucidated the mechanism by which cisplatin exploits the ceramide to render cancer cell apoptosis leading to the abrogation of malignancy in a PKCδ independent pathway with lesser toxicity. Our study revealed that cisplatin treatment in PKCδ silenced melanoma cells induces ceramide mediated apoptosis. Moreover, cisplatin induced upregulation of the transcription factor IRF1 leading to the induction of the transcriptional activity of the TNFα promoter was evident from the pharmacological inhibition and RNA interference studies. Increased cellular expression of TNFα resulted in an elevated ceramide generation by stimulating acid-sphingomyelinase and cPLA2. Furthermore, reciprocity in the regulation of sphingosine kinase 1 (Sphk1) and sphingosine kinase 2 (Sphk2) during PKCδ independent ceramide generation was also observed during cisplatin treatment. PKCδ inhibited murine melanoma model showed reduction in nephrotoxicity along with tumor regression by ceramide generation. Altogether, the current study emphasized the unexplored signaling cascade of ceramide generation by cisplatin during PKCδ silenced condition, which is associated with increased TNFα generation. Our findings enlightened the detailed mechanistic insight of ceramide mediated signaling by chemotherapeutic drugs in cancer therapy exploring a new range of targets for cancer treatment strategies.
Highlights
Malignant neoplasm, commonly known as cancer, is a well known life threatening disease and among its diverse classification melanoma is largely considered to be a chemotherapy refractory tumor [1, 2]
In order to determine the pathway of ceramide generation, protein kinase Cδ (PKCδ) deficient B16F10 melanoma cells were treated with fumonisin B1 (FB1) (10μM) or imipramine (10μM), the well-known inhibitors of de novo and acid sphingomyelinase (ASMase) pathway respectively following cisplatin treatment
Our results confirmed that the ceramide which is produced by sphingomyelinase pathway is involved in cisplatin mediated apoptosis of PKCδ deficient B16F10 melanoma cells
Summary
Commonly known as cancer, is a well known life threatening disease and among its diverse classification melanoma is largely considered to be a chemotherapy refractory tumor [1, 2]. There is a need of detailed mechanistic study of cellular pathways related to available treatments [3,4,5]. In the past two decades, studies on sphingolipids revealed the important role of its bioactive forms such as ceramide, in the regulation of multiple biological functions especially in apoptosis [6, 7]. For effective cancer therapy development, ceramide metabolic pathways have become a major concern. Anti-carcinogenic effect of ceramide in the treatment of malignancy depends on the stimulation of diverse apoptotic pathways
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