کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5527283 1401576 2017 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Autophagy suppression sensitizes glioma cells to IMP dehydrogenase inhibition-induced apoptotic death
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Autophagy suppression sensitizes glioma cells to IMP dehydrogenase inhibition-induced apoptotic death
چکیده انگلیسی


- The role of autophagy in the cytotoxicity of IMPDH inhibitor ribavirin was assessed.
- Ribavirin induced both apoptosis and autophagy in U251 glioma cells.
- Ribavirin induced autophagy by inhibiting IMPDH and Akt/mTORC1 signaling.
- Autophagy inhibition sensitized glioma cells to ribavirin-triggered apoptotic death.

We investigated the role of autophagy, a process of controlled self-digestion, in the in vitro anticancer action of the inosine monophosphate dehydrogenase (IMPDH) inhibitor ribavirin. Ribavirin-triggered oxidative stress, caspase activation, and apoptotic death in U251 human glioma cells were associated with the induction of autophagy, as confirmed by intracellular acidification, appearance of autophagic vesicles, conversion of microtubule associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, and degradation of autophagic target p62/sequestosome 1. Ribavirin downregulated the activity of autophagy-inhibiting mammalian target of rapamycin complex 1 (mTORC1), as indicated by a decrease in phosphorylation of the mTORC1 substrate ribosomal p70S6 kinase and reduction of the mTORC1-activating Src/Akt signaling. Guanosine supplementation inhibited, while IMPDH inhibitor tiazofurin mimicked ribavirin-mediated autophagy induction, suggesting the involvement of IMPDH blockade in the observed effect. Autophagy suppression by ammonium chloride, bafilomycin A1, or RNA interference-mediated knockdown of LC3 sensitized glioma cells to ribavirin-induced apoptosis. Ribavirin also induced cytoprotective autophagy associated with Akt/mTORC1 inhibition in C6 rat glioma cells. Our data demonstrate that ribavirin-triggered Akt/mTORC1-dependent autophagy counteracts apoptotic death of glioma cells, indicating autophagy suppression as a plausible therapeutic strategy for sensitization of cancer cells to IMPDH inhibition.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Cell Research - Volume 350, Issue 1, 1 January 2017, Pages 32-40
نویسندگان
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