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Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance

Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate (Milan 20090), Italy
Author to whom correspondence should be addressed.
These authors equally contributed to the work.
Int. J. Mol. Sci. 2014, 15(3), 4356-4392;
Received: 20 December 2013 / Revised: 7 February 2014 / Accepted: 21 February 2014 / Published: 12 March 2014
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8)αNeu5Ac(2-3)βGal(1-4)βGlc(1-1)Cer) or N-glycolyl GM3 (αNeu5Ac (2-3)βGal(1-4)βGlc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)βGal(1-4)βGlc(1-1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy. View Full-Text
Keywords: sphingolipids; ceramide; sphingosine-1P; gangliosides; globosides; sialidases sphingolipids; ceramide; sphingosine-1P; gangliosides; globosides; sialidases
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Giussani, P.; Tringali, C.; Riboni, L.; Viani, P.; Venerando, B. Sphingolipids: Key Regulators of Apoptosis and Pivotal Players in Cancer Drug Resistance. Int. J. Mol. Sci. 2014, 15, 4356-4392.

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