Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells
Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells
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DOI：
10.1007/s00280-015-2915-4
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发表时间：
2016-01-01
影响因子：
3
通讯作者：
Yuan, Huiqing
中科院分区：
文献类型：
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作者：
Liu, Yongqing;Wang, Ming;Yuan, Huiqing
Malformin A(1) （MA(1)）是一种从真菌中分离出来的环五肽，已被发现可诱导多种有趣的生物活性。在这里，我们报道了MA(1)通过诱导前列腺癌（PCa）细胞凋亡、坏死和自噬介导的细胞毒性的机制模式。用MA处理人PCa细胞PC3和LNCaP(1)，分别分析细胞活力、凋亡、坏死、线粒体损伤、氧化应激和自噬。然后使用药物抑制剂、质粒和sirna的瞬时转染来鉴定氧化应激和自噬在MA(1)引发的细胞死亡中的作用。在PC3和LNCaP细胞中，MA(1)通过活性氧的快速积累和线粒体跨膜电位的降低抑制细胞增殖并引发氧化应激。MA(1)对线粒体的损伤分别触发caspase激活和细胞内ATP缺失，导致细胞凋亡和坏死。同时，MA(1)激活自噬，LC3BI转化为LC3BII，增加gfp标记的LC3B点。药物抑制自噬或敲低LC3B可减轻MA(1)介导的细胞死亡。过度的氧化应激和减少的ATP刺激AMPK/mTOR通路，导致诱导MA(1)介导的自噬。线粒体损伤诱导的凋亡、坏死和自噬细胞死亡的相互作用确定了一种抑制前列腺癌细胞MA生长的新机制(1)，激活自噬可能是提高其化疗效果的潜在策略。
Malformin A(1) (MA(1)), a cyclopentapeptide isolated from fungal origin, has been identified to induce varieties of intriguing biological activities. Here, we reported the mode of mechanism underlying MA(1)-mediated cytotoxicity through induction of apoptosis, necrosis and autophagy in prostate cancer (PCa) cells.Human PCa cells PC3 and LNCaP were treated with MA(1), and cell viability, apoptosis, necrosis, mitochondrial damage, oxidative stress and autophagy were analyzed, respectively. Pharmacological inhibitors, transient transfection of plasmids and siRNAs were then used to identify the roles of oxidative stress and autophagy in MA(1)-triggered cell death.In both PC3 and LNCaP cells, MA(1) inhibited cell proliferation and triggered oxidative stress via the rapid accumulation of reactive oxygen species and a decrease in mitochondrial transmembrane potential. Mitochondrial damage by MA(1) triggered caspase activation and intracellular ATP deletion, leading to apoptosis and necrosis, respectively. Meanwhile, MA(1) activated autophagy as indicated by conversion of LC3BI to LC3BII and increased GFP-tagged LC3B punctate dots. Pharmacological inhibition of autophagy or knocking down LC3B attenuated MA(1)-mediated cell death. Excessive oxidative stress and decreased ATP stimulated AMPK/mTOR pathway, which led to induction of MA(1)-mediated autophagy.Coaction of apoptotic, necrotic and autophagic cell death induced by mitochondrial damage defines a novel mechanism contributing to the growth suppression of MA(1) in prostate cancer cells, and activation of autophagy might be a potential strategy for improving its chemotherapeutic effects.