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Sphingolipids’ Role in Radiotherapy for Prostate Cancer

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Sphingolipids in Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 216))

Abstract

There are several well-established mechanisms involved in radiation-induced cell death in mammalian cell systems. The p53-mediated apoptotic pathway is the most widely recognized mechanism (Lowe et al. Nature 362:847–849, 1993), although apoptosis has long been considered a less relevant mechanism of radiation-induced cell death (Steel, Acta Oncol 40:968–975, 2001; Brown and Wouters, Cancer Res 59:1391–1399, 1999; Olive and Durand, Int J Radiat Biol 71:695–707, 1997). We and others have recently focused instead on the emerging links between radiation, apoptosis, and ceramide and showed that ceramide is a sphingolipid-derived second messenger capable of initiating apoptotic cascades in response to various stress stimuli, including radiation.

Ceramide, the backbone of all sphingolipids, is synthesized by a family of ceramide synthases (CerS), each using acyl-CoAs of defined chain length for N-acylation of the sphingoid long-chain base. Six mammalian CerS homologs have been cloned that demonstrated high selectivity towards acyl-CoAs (Lahiri et al. FEBS Lett 581:5289–5294, 2007), and more recently, it was shown that their activity can be modulated by dimer formation (Mesicek et al. Cell Signal 22:1300–1307, 2010; Laviad et al. J Biol Chem 283:5677–5684, 2008).

This de novo ceramide synthesis has been observed in irradiated cells through a pathway normally suppressed by ataxia telangiectasia-mutated (ATM) protein, a key component of the cellular response to DNA double-strand breaks (Liao et al. J Biol Chem 274:17908–17917, 1999). ATM is not the sole factor known to affect apoptotic potential by modulating CerS activity. Recent work has also implicated protein kinase Cα (PKCα) as a potential CerS activator (Truman et al. Cancer Biol Ther 8:54–63, 2009).

In this review, we summarize involvement of CerS in sphingolipid-mediated apoptosis in irradiated human prostate cancer cells and discuss future directions in this field.

The authors have no conflict of interest or financial ties to disclose.

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Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Carla Hajj & Adriana Haimovitz-Friedman

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  1. Carla Hajj
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  2. Adriana Haimovitz-Friedman
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Correspondence to Adriana Haimovitz-Friedman .

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  1. , Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany

    Erich Gulbins

  2. Division of Pulmonary, Allergy, Critical, Department of Medicine, Indiana University School of Medicine, W. Walnut Street 980, Indianapolis, 46202, Indiana, USA

    Irina Petrache

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Hajj, C., Haimovitz-Friedman, A. (2013). Sphingolipids’ Role in Radiotherapy for Prostate Cancer. In: Gulbins, E., Petrache, I. (eds) Sphingolipids in Disease. Handbook of Experimental Pharmacology, vol 216. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1511-4_6

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