Sphingolipids in Disease

Carla Hajj, Adriana Haimovitz-Friedman, Hajj, Carla, Haimovitz-Friedman, Adriana

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.