Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.
Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.
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DOI：
10.1038/cddis.2013.85
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发表时间：
2013-03-28
影响因子：
9
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中科院分区：
文献类型：
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多形性胶质母细胞瘤（GBM）是最致命和最常见的恶性人类脑肿瘤。高侵袭性 GBM 细胞对放疗和化疗诱导的细胞凋亡的内在抵抗力是导致治疗结果普遍不佳的原因。这项研究调查了奥菲博林 A (OP-A)，一种来自双极菌属的真菌代谢产物，其对人 GBM 细胞具有良好的抗癌活性，对促凋亡刺激表现出不同程度的抵抗力。我们发现OP-A可能通过抑制大电导Ca2+激活的K+通道（BKCa）通道活性，诱导F-肌动蛋白细胞骨架的动态组织发生显着变化，并抑制GBM细胞的增殖和迁移。此外，我们的结果表明，OP-A 诱导 GBM 细胞中的类凋亡样细胞死亡，这与空泡化相关，这可能是由线粒体和/或内质网 (ER) 的肿胀和融合引起的。此外，OP-A诱导的细胞死亡不涉及半胱天冬酶的激活。我们还表明，与这两种细胞器（线粒体和 ER）共定位的 BKCa 通道的表达在这种程序性细胞死亡途径中受到影响。因此，这项研究揭示了一种与 OP-A 抗癌作用相关的新作用机制，其中涉及通过破坏内部钾离子稳态来诱导细胞凋亡。我们的研究结果提供了一种有前景的治疗策略，可以克服 GBM 细胞对促凋亡刺激的内在抵抗力。
Glioblastoma multiforme (GBM) is the most lethal and common malignant human brain tumor. The intrinsic resistance of highly invasive GBM cells to radiation- and chemotherapy-induced apoptosis accounts for the generally dismal treatment outcomes. This study investigated ophiobolin A (OP-A), a fungal metabolite from Bipolaris species, for its promising anticancer activity against human GBM cells exhibiting varying degrees of resistance to proapoptotic stimuli. We found that OP-A induced marked changes in the dynamic organization of the F-actin cytoskeleton, and inhibited the proliferation and migration of GBM cells, likely by inhibiting big conductance Ca2+-activated K+ channel (BKCa) channel activity. Moreover, our results indicated that OP-A induced paraptosis-like cell death in GBM cells, which correlated with the vacuolization, possibly brought about by the swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). In addition, the OP-A-induced cell death did not involve the activation of caspases. We also showed that the expression of BKCa channels colocalized with these two organelles (mitochondria and ER) was affected in this programmed cell death pathway. Thus, this study reveals a novel mechanism of action associated with the anticancer effects of OP-A, which involves the induction of paraptosis through the disruption of internal potassium ion homeostasis. Our findings offer a promising therapeutic strategy to overcome the intrinsic resistance of GBM cells to proapoptotic stimuli.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
3.5
作者：
Calenda, Giulia;Suadicani, Sylvia Ottilie;Davies, Kelvin Paul
通讯作者：
Davies, Kelvin Paul
影响因子：
7.3
作者：
Lallemand, Benjamin;Chaix, Fabien;Kiss, Robert
通讯作者：
Kiss, Robert
影响因子：
8.4
作者：
Megalizzi, Veronique;Decaestecker, Christine;Kiss, Robert
通讯作者：
Kiss, Robert
DOI：
10.1152/nips.01387.2002
发表时间：
2002-08-01
期刊：
NEWS IN PHYSIOLOGICAL SCIENCES
影响因子：
--
作者：
Orio, P;Rojas, P;Latorre, R
通讯作者：
Latorre, R