Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Abstract

In this study, quantitative isobologram studies showed that treatment with gemcitabine and doxorubicin, known inducers of ceramide generation, in combination, supraadditively inhibited the growth of human UM-SCC-22A cells in situ. Then, possible involvement of the human homologue of yeast longevity assurance gene 1 (LASS1)/ C 18 -ceramide in chemotherapy-induced cell death in these cells was examined. Gemcitabine/doxorubicin combination treatment resulted in the elevation of mRNA and protein levels of LASS1 and not LASS2-6, which was consistent with a 3.5-fold increase in the endogenous (dihydro)ceramide synthase activity of LASS1 for the generation of C 18 -ceramide. Importantly, the overexpression of LASS1 (both human and mouse homologues) enhanced the growth-inhibitory effects of gemcitabine/ doxorubicin with a concomitant induction of caspase-3 activation. In reciprocal experiments, partial inhibition of human LASS1 expression using small interfering RNA

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

“…It is very well-known that both exogenously applied C8-ceramide, PDMP, and SK-1 inhibitors elevate endogenous ceramide concentrations in various types of cancers [9,30]. In this study, we documented that inhibition of GCS and SK-1 with specific chemical inhibitors and exogenous C8:ceramide application inhibited cell proliferation and induced apoptosis in a dose-dependent manner in both K562 and Meg-01 CML cells.…”

“…We combined increasing concentrations of dasatinib with IC10 values of PDMP and SK-1 inhibitor since we have previously shown that IC10 values of these chemicals are enough to inhibit the enzyme activities and provide accumulation of ceramides in the cells [9]. In parallel experiments, we combined IC50 value of C8: ceramide with increasing concentrations of dasatinib since ceramide analogs trigger induction of generation of apoptotic ceramides at IC50 value [30]. The magic behind these experiments was to determine possible synergistic antiproliferative effects dasatinib on K562 and Meg-01 cells in which intracellular ceramide concentrations were increased.…”

Plasma sphingolipids and depressive symptoms in coronary artery disease

“…found an association between ceramide C18:0 and depressive symptom severity in their study population (Demirkan et al., 2013). Importantly, both species have been implicated in apoptosis (Babenko, Hassouneh, Budvytiene, Liesiene, & Geilen, 2010; Cremesti et al., 2001; Grassme et al., 2001; Senkal et al., 2007; Thomas, Matsko, Lotze, & Amoscato, 1999). For ceramide C16:0, concentrations were found to be elevated in apoptotic cells within 2 hr of being exposed to ionizing radiation (Thomas et al., 1999).…”

“…C18:0 has been observed to induce apoptosis of keratinocytes in a concentration‐dependent manner (Babenko et al., 2010). In addition, concentrations of C18:0 were found to be elevated in chemotherapy‐induced apoptosis (Senkal et al., 2007). As both C16:0 and C18:0 may be proapoptotic, it is feasible that elevated concentrations of these species may contribute to neurodegeneration in depression.…”

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

“…Ceramide is an intracellular lipid that has been shown to regulate the activity of various biochemical and molecular targets involved in anti-proliferative responses and in cellular responses including oxidative stress and apoptosis [20,21]. The biological effects of ceramide depend on many parameters, such as cell type, nature of cell receptors, and their concentration [22].…”