Browsing by Subject "eIF3a"

Now showing 1 - 3 of 3
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    Effect of eIF3a on response of lung cancer patients to platinum-based chemotherapy by regulating DNA repair
    (American Association for Cancer Research, 2011) Yin, Ji-Ye; Shen, Jie; Dong, Zi-Zheng; Huang, Qiong; Zhong, Mei-Zuo; Feng, De-Yun; Zhou, Hong-Hao; Zhang, Jian-Ting; Liu, Zhao-Qian; Pharmacology and Toxicology, School of Medicine
    Purpose: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNA-damaging anticancer drugs. Experimental design: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression. Results: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins. Conclusions: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA-damaging anticancer drugs and patients' response to platinum-based chemotherapy.
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    eIF3a Regulates De Novo Fatty Acid Synthesis as an Alternative Mechanism in Cisplatin Response in Non-Small Cell Lung Cancer Cells
    (2024-08) Gu, Boqing; Jerde, Travis; Lu, Tao; Safa, Ahmad R.; Zhang, Jian-Ting; Wek, Ronald C.
    eIF3a is known to modulate DNA damage repair and cancer chemotherapy resistance partially via translational regulation of Raptor and its downstream mTOR pathway activity. Fatty acid synthase (FASN) has recently been reported to exert negative feedback on the mTOR signaling pathway, and FASN overexpression is associated with reduced chemotherapy efficiency in multiple cancer types. Here, we show that eIF3a exerts additional regulation on mTOR signaling pathway and chemotherapy resistance in non-small cell lung cancer by inhibiting FASN-mediated de novo lipid synthesis. Through genetic and chemical manipulations, we demonstrate that eIF3a physically interacts with the 5’-UTR of FASN mRNA to prevent FASN protein synthesis. Furthermore, FASN downregulation by eIF3a results in accumulation of malonyl-CoA, a substrate for fatty acid synthesis, which in turn directly inhibits mTOR activity of mTORC1 complex, decreasing NER protein level and cellular sensitivity to cisplatin in an eIF3a-dependent manner in addition to eIF3a-regulated expression of Raptor subunit in mTORC1. Taken together, our findings reveal a direct translational control of FASN-mediated fatty acid metabolism, suggesting a multi-level eIF3a regulatory paradigm on NER protein synthesis and activity during cancer cell response to cisplatin treatment.
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    Role of eIF3a in regulating cell cycle progression
    (Elsevier, 2009) Dong, Zizheng; Liu, Zhaoqian; Cui, Ping; Pincheira, Roxana; Yang, Youyun; Liu, Jianguo; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine
    Translational control is an essential process in regulation of gene expression, which occurs at the initiation step performed by a number of translation initiation factor complexes. eIF3a (eIF3 p170) is the largest subunit of the eIF3 complex. eIF3a has been suggested to play roles in regulating translation of a subset of mRNAs and in regulating cell cycle progression and cell proliferation. In this study, we examined the expression profile of eIF3a in cell cycle and its role in cell cycle progression. We found that eIF3a expression oscillated with cell cycle and peaked in S phase. Reducing eIF3a expression also reduced cell proliferation rate by elongating cell cycle but did not change the cell cycle distribution. However, eIF3a appears to play an important role in cellular responses to external cell cycle modulators likely by affecting synthesis of target proteins of these modulators.