While these data clearly support the involvement of Scd1 as a central regulator of lipogenesis in cancer cells, the link between Scd1 and the induction of ER stress and cell death in cancer cells remains to be better understood. However, in a severe or prolonged stress, the UPR can trigger pro-apoptotic signals through activation of the transcription factor CHOP, which acts to repress the bcl-2 gene expression, thus down-regulating anti-apoptotic Bcl-2 protein and rendering cells sensitive to the pro-apoptotic effects of BH3-only proteins,. IRE1α disposes of an endoribonuclease activity that alternatively splices the Xbp1 mRNA (sXbp1), which is translated into an active transcription factor. Then cleaved ATF6 localises to the nucleus and induces transcription of Xbp1 and ER chaperones such as GRP78. Active ATF6 translocates to the Golgi and is cleaved from the membrane by site-1 and -2 proteases. PERK phosphorylates the eukaryotic translation initiation factor (eIF)2α, thereby inhibiting global protein synthesis. In stressed cells, the chaperone protein GRP78 dissociates from UPR sensors PERK, ATF6 and IRE1α leading to their activation to first alleviate ER stress. Activation of the canonical UPR engages three distinct concerted signalling branches mediated by ER membrane anchored sensors: RNA-dependent protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1α (IRE1α). CHOP belongs to a peculiar stress pathway named endoplasmic reticulum (ER) stress that may induce apoptosis.ĮR stress is triggered by different stress conditions such as alterations in post-translational protein status and lipid synthesis, hypoxia, disruption of calcium homeostasis and nutrient deprivation, and leads to the activation of an adaptive program, known as the Unfolded Protein Response (UPR), to re-establish equilibrium. The alteration of lipid production in Scd1-deficient cells mainly concerns a reduction of phospholipid biosynthesis, which triggers cellular stress and expression of the apoptosis-related protein C/EBP homologous protein (CHOP/GADD153),. Furthermore, different cancer cells lacking Scd1 activity reduce de novo lipogenesis through activation of the AMPK pathway. oleic acid) for sustaining cell proliferation and survival. Indeed, in absence of Scd1, the SFA content increases which alleviates Akt activation normally obtained by MUFA (e.g. The mechanism of cell death observed in Scd1-deficient lung cancer cells seems to involve the modification of a SFA/MUFA ratio that triggers inhibition of the Akt pathway and activation of the AMPK pathway. Indeed, Scd1 over-expressing cells present a growth advantage while scd1 knock-down leads to slower rates of cell proliferation and cell death in vivo and in vitro,. Thus, Scd1 expression can be related to carcinogenesis processes involving alteration of proliferation/apoptosis balance. For prostate cancer, two studies present contradictory results on Scd1 expression level. Scd1 expression, correlated with MUFA content, is increased in hepatocellular adenoma, colonic and oesophageal carcinoma, as well as in genetically- and chemically-induced tumors. Scd1 is found in almost all tissues with a major expression in liver while Scd5 expression is restricted to pancreas and brain. This endoplasmic reticulum resident enzyme exists under two isoforms in humans, Scd1 and Scd5.
Indeed, Scd catalyzes the introduction of a double bond between carbons 9 and 10 of several saturated fatty acids such as palmitic (16∶0) and stearic (18∶0) acids to yield palmitoleic (16∶1) and oleic (18∶1) acids, respectively. Increased MUFA content could be also due to an up-regulation of stearoyl Co-A desaturase (Scd, delta-9 desaturase) expression, the rate-limiting enzyme of MUFA synthesis. Thus, overexpression of acetyl Co-A carboxylase α and fatty acid synthase, involved in the first steps of fatty acid biosynthesis, were described in various cancers, ,, ,. These modifications of SFA and MUFA content are associated with the modulation of the expression and activity of lipogenic enzymes. Changes in lipid membrane composition are observed in a wide variety of cancers, mainly characterised by saturated (SFA) and monounsaturated fatty acid (MUFA) accumulation which appears less due to increased uptake of SFA and MUFA than to exacerbated endogenous fatty acids synthesis, irrespective of adequate lipid nutritional supply, ,, ,. Active proliferating cancer cells present not only quantitative changes in de novo lipid biosynthesis but also modifications of lipid membrane composition affecting membrane fluidity, signal transduction and gene expression. Cancer cells exhibit metabolism alterations characterised by increased glycolysis and lipogenesis.
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