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Involvement of MGr1-Ag/37LRP in the vincristine-induced HIF-1 expression in gastric cancer cells

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Abstract

Drug resistance is a major obstacle in the development of effective cancer therapy. It was reported that many chemotherapeutic drugs such as vincristine (VCR), a potent anti-tumor agent that associates with microtubules and disrupts the microtubular system, was found in acquisition of drug-resistance associated with an increase of HIF−1 expression via activating the NF-γB signal pathway. However, the multifactorial mechanism responsible for VCR increased HIF−1α expression remains to be fully elucidated. MGr1−Ag was previously reported by our laboratory as an upregulated protein in VCR-resistant cell lines SGC7901/VCR. In our study, detection of HIF−1 expression in SGC7901 cells and SGC7901/VCR cell or VCR-treated SGC7901cells showed that VCR could induce a significant expression of HIF−1α and VCR-resistant SGC7901/VCR cells had much higher expression of HIF−1α. Under nonhypoxic condition, VCR could enhance DNA binding activity and transcriptional activity of HIF−1α by 5.42− and 9.42-fold, respectively. Further study showed that forced expression of MGr1-Ag/37LRP upregulated HIF−1α protein expression and transcriptional activity in gastric cancer cell under nonhypoxic condition whereas siRNA targeting MGr1-Ag showed a markedly decreased VCR-induced HIF−1α expression and transcriptional activity (P < 0.05). SiRNA targeting FAK or inhibitors of phosphatidylinositol 3-kinase (PI3K) and MAPK could inhibit VCR-induced HIF−1α expression, suggesting FAK-PI3K and p42/44MAPK (Erk1/2) may be the major signaling molecules in MGr1-Ag/37LRP-induced HIF−1α expression and activity. These data support a model in which MGr1-Ag was a focal point for the convergence of VCR-mediated signaling events leading to HIF−1Α induction, thus revealing a novel aspect of HIF−1α regulation.

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Acknowledgments

National Nature Science Foundation of China (Number: 30400541) and National Basic Research Program of China, No.2006CB504100 supported this study.

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Authors and Affiliations

  1. State Key Laboratory of Cancer Biology, Institute of Digestive Diseases Xijing Hospital, Fourth Military Medical University, No. 15 Chang le West Road, Xi’an, 710032, P.R. China

    Lili Liu, Xiaoxuan Ning, Li Sun, Yongquan Shi, Shuang Han, Changcun Guo, Yu Chen, Shiren Sun, Fang Yin, Kaichun Wu & Daiming Fan

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  1. Lili Liu
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  2. Xiaoxuan Ning
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  3. Li Sun
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Correspondence to Kaichun Wu.

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Lili Liu and Xiaoxuan Ning contributed to this work equally.

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Liu, L., Ning, X., Sun, L. et al. Involvement of MGr1-Ag/37LRP in the vincristine-induced HIF-1 expression in gastric cancer cells. Mol Cell Biochem 303, 151–160 (2007). https://doi.org/10.1007/s11010-007-9467-9

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  • DOI: https://doi.org/10.1007/s11010-007-9467-9

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