کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
4303032 1288469 2010 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Targeting Bcl-2-Mediated Cell Death as a Novel Therapy in Pancreatic Cancer
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی عمل جراحی
پیش نمایش صفحه اول مقاله
Targeting Bcl-2-Mediated Cell Death as a Novel Therapy in Pancreatic Cancer
چکیده انگلیسی

BackgroundBcl-2 is an essential regulator of programmed cell death (PCD). Overexpression of Bcl-2 is common in pancreatic cancer; the high levels have been shown to correlate with resistance to PCD. This resistance is mediated by binding of Bcl-2 via its BH-3 domain to diverse proteins, including the Bax/Bak family members, various protein kinases, and beclin 1, which are involved in regulation of autophagy (type II PCD). Small molecule inhibitors of BH-3-mediated binding of Bcl-2 have been recently developed, although no investigation has been conducted in pancreatic cancer, a malignancy characterized by extreme resistance to PCD.MethodsThe effect of the Bcl-2 binding inhibitor A-779024 on PCD was assessed by fluorescence activated cell sorting; the effect on Bcl-2 and other PCD-related proteins was analyzed by immunoblotting. Induction of autophagy was determined by fluorescence microscopy using a stably transfected GFP-LC3 construct to visualize autophagosome formation. Co-localization of Bcl-2 with binding partners regulating PCD was examined by immunoprecipitation and confocal immunofluorescent microscopy.ResultsA-779024 induced PCD in a dose- and time-dependent fashion. No change was seen in the protein levels of Bcl-2, Bax, Bcl-XL, or Mcl-1. Contrary to prediction, A-779024 was ineffective at inducing autophagy in these cells. Co-localization studies demonstrated that Bcl-2 was not bound to beclin 1 and, therefore, treatment with A-779024 could not induce release of beclin 1 and initiation of autophagy.ConclusionsDisruption of Bcl-2 activity using the small molecule inhibitor A-779024 induces apoptotic but not autophagic PCD. This approach may be a novel therapy, either alone or in combination with other treatments such as chemotherapy or autophagy modulating agents in pancreatic cancer.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Surgical Research - Volume 163, Issue 2, October 2010, Pages 276–281
نویسندگان
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