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مقالات فارسیISIکنفرانسهاژورنالها

Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib

محل انتشار: مجله گزارش های بیوشیمی و زیست شناسی مولکولی، دوره: 12، شماره: 1
سال انتشار: 1402
نوع سند: مقاله ژورنالی
زبان: انگلیسی
مشاهده: 137

فایل این مقاله در 9 صفحه با فرمت PDF قابل دریافت می باشد

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لینک ثابت به این مقاله:
https://civilica.com/doc/1735996

شناسه ملی سند علمی:

JR_RBMB-12-1_007

تاریخ نمایه سازی: 31 مرداد 1402

چکیده مقاله:

Background: Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI۳ kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. Methods: The frequently seen primary KIT mutations W۵۵۷K۵۵۸del and V۵۶۰D, and the secondary KIT mutations V۶۵۴A and N۸۲۲K, in gastrointestinal stromal tumors were stably transfected into Ba/F۳ cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot. Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

کلیدواژه ها:

Farnesyltransferase ، Imatinib ، KIT ، RAS.

نویسندگان

Zhaoyang Fan

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Liangying Zhang

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Shaoting Zhang

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Anbu Liu

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Shujing Li

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China & General Hospital of Ningxia Medical University, Yinchuan, China.

Xu Cao

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Jinhai Tian

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China & General Hospital of Ningxia Medical University, Yinchuan, China.

Sien Zhao

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

Jianmin Sun

NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.

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