Involvement of MGr1-Ag/37LRP in the vincristine-induced HIF-1 expression in gastric cancer cells
详细信息 查看全文
- 作者：Lili Liu ; Xiaoxuan Ning ; Li Sun ; Yongquan Shi ; Shuang Han ; Changcun Guo ; Yu Chen ; Shiren Sun ; Fang Yin and Kaichun Wu ; et al.
- 关键词：Vincristine ; Hypoxia ; inducible factor− ; 1 ; MGr1 ; Ag/37LRP ; Gastric cancer
- 刊名：Molecular and Cellular Biochemistry
- 出版年：2007
- 出版时间：September, 2007
- 年：2007
- 卷：303
- 期：1-2
- 页码：151-160
- 全文大小：397 KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Life Sciences
Biochemistry
Medical Biochemistry
Oncology
Cardiology - 出版者：Springer Netherlands
- ISSN：1573-4919
文摘
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.