Dysregulation of sphingolipid metabolism in cancer

Abstract

Altered sphingolipid metabolism contributes to cancer progression and presents an exploitable target for the development of novel chemotherapeutics. Bioactive sphingolipid metabolites also have the potential to serve as vital biomarkers for cancer and be utilized to determine disease progression, as well as guide therapeutic regimens. Moreover, identification of these sphingolipid biomarkers is achievable based on recent technological advances in sphingolipidomics, which have aided in detection of sphingolipid metabolites through tools like mass spectrometry. Excellent reviews have previously focused on the biochemical role that sphingolipids have in cancer pathogenesis and treatment. The aim of this review is to concentrate on the critical metabolites and enzymes that contribute to the dysregulation in sphingolipid metabolism, and highlight relevant translational research that is directed towards novel therapies.

Large-scaled human serum sphingolipid profiling by using reversed-phase liquid chromatography coupled with dynamic multiple reaction monitoring of mass spectrometry: Method development and application in hepatocellular carcinoma

“…In addition, SM species were observed to be inconsistently altered. Dysregulation in sphingolipid homeostasis has been recognized to contribute to cancer pathogenesis [9,[38][39][40], and its modulation has merged as a potential target for anticancer therapy [41,42].…”

“…Cer, ceramide; dHCer, dihydroceramide; SM, sphingomyelin; HexCer, hexosylceramide; LacCer, lactosylceramide. diabetes, cardiovascular disease, and various cancer diseases as well as central nervous system diseases [7][8][9][10]. To expand our knowledge of this lipid family, development of sensitive, robust and structural-specific methods enabling fast determination of as many sphingolipid species as possible are required.…”

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

“…In the case of complex II, for example, it was demonstrated that during ischaemia/reperfusion, superoxides can induce a loss of SDHA glutathionylation favouring its nitration by peroxynitrite on tyrosine residues, leading to an impairment of its activity (Chen et al, 2007b(Chen et al, , 2008. Finally, besides ROS, pH, calcium, other second messengers frequently misregulated in cancer were shown to control the RC, notably nitric oxide and ceramide, a sphingolipid involved in mitochondrial apoptotic signalling and in the response to anticancer agents (Siskind, 2005;Ryland et al, 2011) (Table 1).…”

“…A good candidate to make the link between defective RCC function and apoptosis are ROS, as they are often formed when RCCs are partially inhibited. These ROS, which can also be generated in physiological conditions, are (Clementi et al, 1998;Fiorucci et al, 2004) (3) Ceramide synthesis: or depending on cancer type (Ryland et al, 2011) Direct RCC III inhibition and subsequent ROS production (Gudz et al, 1997;Di Paola et al, 2000) Abbreviations: NO, nitric oxide; O 2 , oxygen; RCC, respiratory chain complex; ROS, reactive oxygen species.…”

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

“…4,5 Physiological levels of circulating S1P are vasculoprotective, whereas abnormal activation of SphK/S1P signaling is associated with diseases such as cancer, fibrosis, diabetes, and hypertension. [6][7][8][9][10] At high cellular or tissue levels, S1P is a proproliferative, antiapoptotic, promigratory, profibrotic, and proinflammatory signaling molecule. 11 SphK activity and S1P production are stimulated by numerous signals, including growth factors, cytokines, mitogens, and G protein-coupled receptor agonists.…”