Induction of ER stress-mediated apoptosis by ceramide via disruption of ER Ca2+ homeostasis in human adenoid cystic carcinoma cells

Abstract

BackgroundCeramides are a class of sphingolipids that form the structural component of the cell membrane and also act as second messengers in cell signaling pathways. Emerging results suggest that ceramide induces growth arrest and apoptosis in various human cancer cells. However, the mechanisms underlying its antitumor activity are yet to be identified. Endoplasmic reticulum stress (ER stress), a cellular adaptive response, is believed to initially compensate for damage but can eventually trigger cell death if the stimulus is severe or prolonged. In this study, we investigated whether ceramide induces cell death in human salivary adenoid cystic carcinoma (ACCs) through activation of the apoptotic ER stress.ResultsRT-PCR, real-time PCR and western blot demonstrated that exogenous ceramide treatment up-regulated GRP78 and p-eIF2α expression and XBP1 splicing. Moreover, the ceramide synthase inhibitor FB1 abolished ceramide-induced ER stress. Up-regulation of the ER stress-associated apoptosis promoting transcription factor CHOP and p-JNK suggested that the antitumor activity of ceramide is owing to activation of apoptotic ER stress. Mechanistically, [Ca2+]ER depletion and SERCA inhibition by ceramide treatment suggested that it induces ER stress by disrupting [Ca2+]ER homeostasis. The chemical chaperone TUDCA inhibited ceramide-induced ER stress and cell death. In addition, the downstream metabolite of ceramide, S1P, cannot activate ER stress.ConclusionsThese results demonstrated that exogenous ceramide induces cancer cell death through a mechanism involving severe ER stress triggered by the disruption of ER Ca2+ homeostasis.

Ceramides and diabetes mellitus: an update on the potential molecular relationships

“…For example, Liu et al . found that exogenous application of ceramides induces severe ER stress by impairing ER Ca 2+ homeostasis in human adenoid cystic carcinoma cells. Yano et al .…”

“…ER stress is a prominent marker of insulin‐resistant cells which, in turn, further impair glucose homeostasis . Ceramides can induce ER stress and impair glucose homeostasis in a number of experimental models in several cell lines, such as islet β cells . For example, Liu et al .…”

“…ER stress is a prominent marker of insulin-resistant cells which, in turn, further impair glucose homeostasis [68]. Ceramides can induce ER stress and impair glucose homeostasis in a number of experimental models in several cell lines, such as islet b cells [68,69]. For example, Liu et al [69] found that exogenous application of ceramides induces severe ER stress by impairing ER Ca 2+ homeostasis in human adenoid cystic carcinoma cells.…”

“…Ceramides can induce ER stress and impair glucose homeostasis in a number of experimental models in several cell lines, such as islet b cells [68,69]. For example, Liu et al [69] found that exogenous application of ceramides induces severe ER stress by impairing ER Ca 2+ homeostasis in human adenoid cystic carcinoma cells. Yano et al [70] showed that ceramides can cause ER stress by inducing protein misfolding in the ER as a result of Ca 2+ depletion in pancreatic b cells.…”

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

“…In line with this, increments in hypothalamic fatty acid oxidation preventing the production of fatty acylglycerols, ceramides, and cholesterol esters can revert ER stress levels, and this reduction in lipotoxicity leads to decreased food intake and body weight, improving systemic metabolism [216] . Mechanistically, it was described in cellular models that ceramides induce ER calcium depletion through SERCA (sarco/endoplasmic reticulum Ca 2+ -ATPase) inhibition, leading to disrupted ER Ca 2+ homeostasis and triggering a UPR [217,218] . Moreover, it was recently demonstrated that ceramide-induced lipotoxicity within the VMH produces a marked increase in body weight and adiposity through a decrease in SNS-mediated BAT thermogenesis [99] .…”