Sphingolipid metabolism in cancer signalling and therapy

Abstract

Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy

“…However, it is well known that endothelial growth factor (EGF)-receptors are activated by lipid rafts and transported by EVs (Al-Nedawi, Meehan, Kerbel, Allison, & Rak, 2009; Pike, 2005). Secretion of sphingosine-1-phosphate (S1P), a ceramide derivative, is instrumental in promoting angiogenesis during tumor growth (Mizugishi et al, 2005; Nagahashi et al, 2012; Ogretmen, 2018; Pyne, El Buri, Adams, & Pyne, 2017; Spiegel & Kolesnick, 2002; Spiegel & Milstien, 2003; Takabe, Paugh, Milstien, & Spiegel, 2008; Takabe & Spiegel, 2014). It was found that stable complexes of S1P with G-protein coupled receptors (GPCRs) are critical for formation of exosomes in MVEs through constitutive activation of Rho GTPases and stabilization of F-actin (Kajimoto et al, 2018).…”

Balance between senescence and apoptosis is regulated by telomere damage–induced association between p16 and caspase-3

“…The slides were washed thrice with 1X PBS pH 7.4 and blocked with 1% goat serum in 0.3M glycine, 1% BSA and 0.1% Tween-20 in 1X PBS, pH7.4 for 2 hours. The cells were then incubated with primary antibodies that recognize g-H2AX (5µg/ml; ab2893, Abcam) and TRF-2 (5µg/ml; IMG-124A, Imgenex) for 18 h. The slides were then washed thrice with 1X PBS, pH7.4 and incubated with secondary antibodies containing Alexa 488, Alexa 594 and Cy5 fluorophores against g-H2AX and TRF-2, respectively for 2 h at [20][21][22][23][24][25] o C. The slides were then washed three times with 1X PBS, pH7.4 and DAPI containing mounting media was added and sealed with glass cover slips (colocalization resulted in either purple or yellow/orange images). Images were captured using IF-CM, and colocalization was quantified using Pearson's correlation coefficient was used to calculate colocalization efficiency and P<0.05 was considered significant by ImageJ Fiji software (27).…”

“…This culture was diluted 1:2000 into 4x250 mL of LB media and incubated at 37 °C until the OD600 reached 3-5. Rich media was exchanged to a minimal formulation suitable for high-density IPTG induction by spinning the cells gently at 5,000 x g for 10 min at [20][21][22][23][24][25] o C, and then resuspending in an equal volume of minimal media. Cultures were incubated at 37 °C until the OD600 increased by at least 1 unit, the incubator was lowered to 18 °C, and protein expression was induced with 1 mM IPTG for 16 h at 170 rpm.…”

“…Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid, generated by sphingosine kinase 1 or 2 (SPHK1 or SPHK2), that exerts prooncogenic signaling via engaging with its Gprotein coupled receptors (S1PR1-5) in an autocrine or paracrine manner, and/or via directly binding to regulate its intracellular target proteins without receptor signaling (22)(23)(24)(25). Intracellular targets of SPHK2-generated nuclear S1P include HDAC1/2 (26) and TERT (27).…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…Therefore, understanding how to better use these new drugs that target sphingolipid metabolism, either alone or in combination with current cancer treatments, holds great potential for cancer control. While sphingolipids in cancer have been reviewed previously (Hannun & Obeid, 2018; Lee & Kolesnick, 2017; Morad & Cabot, 2013; Newton, Lima, Maceyka, & Spiegel, 2015; Ogretmen, 2018; Ryland, Fox, Liu, Loughran, & Kester, 2011) in this chapter, we present a comprehensive review on how standard of care therapeutics affects sphingolipid metabolism, the current landscape of sphingolipid inhibitors, and the clinical utility of sphingolipid-based cancer therapeutics. …”