OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins.
OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins.
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DOI：
10.4161/cbt.9.7.11116
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发表时间：
2010-04-01
影响因子：
3.6
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Hamed HA;Yacoub A;Park MA;Eulitt P;Sarkar D;Dimitrie IP;Chen CS;Grant S;Curiel DT;Fisher PB;Dent P
目前的研究集中于确定自噬诱导药物OSU-03012（AR-12）是否可以增强重组腺病毒递送的黑素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）在多形性胶质母细胞瘤（GBM）细胞中的毒性。表达MDA-7/IL-24的重组腺病毒（Ad. mda-7）的毒性在一组不同的原代人GBM细胞中被OSU-03012增强。增强的毒性与降低的ERK 1/2磷酸化和MCL-1和BCL-XL的表达相关，并且通过ERK 1/2的分子活化和通过抑制内源性而非外源性凋亡途径而被阻断。OSU-03012和MDA-7/IL-24的表达都增加了PKR样内质网激酶（PERK）的磷酸化，这与自噬水平的增加相关，并且显性负性PERK的表达阻断了自噬诱导和肿瘤细胞死亡。ATG5或Beclin1的敲除抑制OSU-03012增强MDA-7/IL-24诱导的自噬，并阻断两种药物之间的致死性相互作用。Ad. mda-7感染的GBM细胞将MDA-7/IL-24分泌到生长培养基中，并且该条件培养基诱导未感染的GBM细胞中MDA-7/IL-24的表达。OSU-03012与条件培养基相互作用以杀死GBM细胞，并且在这些细胞中敲低MDA-7/IL-24抑制肿瘤细胞杀死。总的来说，我们的数据表明，通过组合治疗方法诱导自噬和线粒体功能障碍代表了杀死原代人GBM细胞的潜在可行策略。
The present studies focused on determining whether the autophagy-inducing drug OSU-03012 (AR-12) could enhance the toxicity of recombinant adenoviral delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) in glioblastoma multiforme (GBM) cells. The toxicity of a recombinant adenovirus to express MDA-7/IL-24 (Ad.mda-7) was enhanced by OSU-03012 in a diverse panel of primary human GBM cells. The enhanced toxicity correlated with reduced ERK1/2 phosphorylation and expression of MCL-1 and BCL-XL, and was blocked by molecular activation of ERK1/2 and by inhibition of the intrinsic, but not the extrinsic, apoptosis pathway. Both OSU-03012 and expression of MDA-7/IL-24 increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) that correlated with increased levels of autophagy and expression of dominant negative PERK blocked autophagy induction and tumor cell death. Knockdown of ATG5 or Beclin1 suppressed OSU-03012 enhanced MDA-7/IL-24-induced autophagy and blocked the lethal interaction between the two agents. Ad.mda-7-infected GBM cells secreted MDA-7/IL-24 into the growth media and this conditioned media induced expression of MDA-7/IL-24 in uninfected GBM cells. OSU-03012 interacted with conditioned media to kill GBM cells and knockdown of MDA-7/IL-24 in these cells suppressed tumor cell killing. Collectively, our data demonstrate that the induction of autophagy and mitochondrial dysfunction by a combinatorial treatment approach represents a potentially viable strategy to kill primary human GBM cells.
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DOI：
10.1073/pnas.152327199
发表时间：
2002-07-23
影响因子：
11.1
作者：
Sarkar, D;Su, ZZ;Fisher, PB
通讯作者：
Fisher, PB
影响因子：
8
作者：
Lebedeva, IV;Su, ZZ;Fisher, PB
通讯作者：
Fisher, PB
影响因子：
11.2
作者：
Gupta, Pankaj;Walter, Mark R.;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
6.4
作者：
Ekmekcioglu, S;Ellerhorst, J;Grimm, EA
通讯作者：
Grimm, EA
影响因子：
45.3
作者：
Ellerhorst, JA;Prieto, VG;Grimm, EA
通讯作者：
Grimm, EA