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Acid Ceramidase, a Double-edged Sword in Cancer Aggression: A Mini-review

期刊

CURRENT CANCER DRUG TARGETS
卷 21, 期 3, 页码 177-191

出版社

BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568009620666201223154621

关键词

Acid ceramidase; apoptosis; cancer; cell proliferation; acid ceramidase inhibitor; ceramide; sphingosine-1-phosphate

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资金

  1. University Grant Commission-Maulana Azad Fellowship scheme [F1-17.1/2013-14/MANF-2013-14-CHR-TAM-27309]

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AC plays a critical role in cancer progression, with its upregulation leading to increased cell proliferation, metastasis, chemoresistance, and radioresistance. Gene silencing and pharmacological inhibition of AC can enhance sensitivity of resistant cells to therapy, thereby promoting cell death.
Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway, hydrolyzes pro-apoptotic ceramide to sphingosine, which is metabolized to mitogenic sphingosine-1-phosphate by the action of sphingosine-1-kinase. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat, which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a double-edged sword by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased, and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy, thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

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