Indomethacin impairs mitochondrial dynamics by activating the PKC-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells
Indomethacin impairs mitochondrial dynamics by activating the PKC-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells
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DOI：
10.1074/jbc.ra118.004415
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发表时间：
2019-05-17
影响因子：
4.8
通讯作者：
Bandyopadhyay, Uday
中科院分区：
文献类型：
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作者：
Mazumder, Somnath;De, Rudranil;Bandyopadhyay, Uday
非甾体抗炎药(NSAIDs)诱导胃癌和正常粘膜细胞凋亡的亚细胞机制尚不清楚，因为这些药物具有不同的环氧合酶非依赖性作用。利用人胃癌细胞(AGSS)和大鼠胃损伤模型，我们报道了非甾体抗炎药吲哚美辛通过激活蛋白激酶C(PKC)-p38MAPK(P38)-动力蛋白相关蛋白1(Drp1)通路，通过促进线粒体超分裂和功能障碍导致细胞凋亡，从而破坏了线粒体动力学的生理性平衡。值得注意的是，Drp1基因敲除或SB203580诱导的p38抑制减少了吲哚美辛对AGS的损伤。吲哚美辛通过促进裂隙激活和线粒体募集，下调融合基因视神经萎缩1(OPA1)和胃黏膜中的丝裂蛋白，从而损伤线粒体动力学。与OPA1维持冠突结构一致，其下调导致EM可检测到的冠突畸形。Parkin表达增强和线粒体蛋白质组泛素化是导致缺陷线粒体的线粒体动力学失控的明显原因。吲哚美辛最终在大鼠胃中诱导了线粒体代谢和生物能量危机，表现为脂肪酸氧化受损，复合体I相关电子传输链活性降低，以及ATP耗竭。有趣的是，Mdivi-1，一种防止分裂的丝裂保护药物，逆转了吲哚美辛诱导的Ser-616上DRp1的磷酸化，线粒体蛋白质组泛素化，以及线粒体代谢危机。MDIVI-1还可预防消炎痛引起的线粒体大分子损伤、半胱氨酸天冬氨酸氨基转移酶激活、粘膜炎症和胃粘膜损伤。我们的结果发现，线粒体过度分裂是消炎痛引发的一种关键和常见的亚细胞事件，它促进了胃癌和正常粘膜细胞的凋亡，从而促进了粘膜损伤。
The subcellular mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastric cancer and normal mucosal cells is elusive because of the diverse cyclooxygenase-independent effects of these drugs. Using human gastric carcinoma cells (AGSs) and a rat gastric injury model, here we report that the NSAID indomethacin activates the protein kinase C (PKC)-p38 MAPK (p38)-dynamin-related protein 1 (DRP1) pathway and thereby disrupts the physiological balance of mitochondrial dynamics by promoting mitochondrial hyper-fission and dysfunction leading to apoptosis. Notably, DRP1 knockdown or SB203580-induced p38 inhibition reduced indomethacin-induced damage to AGSs. Indomethacin impaired mitochondrial dynamics by promoting fissogenic activation and mitochondrial recruitment of DRP1 and down-regulating fusogenic optic atrophy 1 (OPA1) and mitofusins in rat gastric mucosa. Consistent with OPA1 maintaining cristae architecture, its down-regulation resulted in EM-detectable cristae deformity. Deregulated mitochondrial dynamics resulting in defective mitochondria were evident from enhanced Parkin expression and mitochondrial proteome ubiquitination. Indomethacin ultimately induced mitochondrial metabolic and bioenergetic crises in the rat stomach, indicated by compromised fatty acid oxidation, reduced complex I- associated electron transport chain activity, and ATP depletion. Interestingly, Mdivi-1, a fission-preventing mito-protective drug, reversed indomethacin-induced DRP1 phosphorylation on Ser-616, mitochondrial proteome ubiquitination, and mitochondrial metabolic crisis. Mdivi-1 also prevented indomethacin-induced mitochondrial macromolecular damage, caspase activation, mucosal inflammation, and gastric mucosal injury. Our results identify mitochondrial hyper-fission as a critical and common subcellular event triggered by indomethacin that promotes apoptosis in both gastric cancer and normal mucosal cells, thereby contributing to mucosal injury.