Involvement of MGr1-Ag/37LRP in the vincristine-induced HIF-1 expression in gastric cancer cells.
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-gammaB signal pathway. However, the multifactorial mechanism responsible for VCR increased HIF-1alpha 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-1alpha and VCR-resistant SGC7901/VCR cells had much higher expression of HIF-1alpha. Under nonhypoxic condition, VCR could enhance DNA binding activity and transcriptional activity of HIF-1alpha by 5.42- and 9.42-fold, respectively. Further study showed that forced expression of MGr1-Ag/37LRP upregulated HIF-1alpha protein expression and transcriptional activity in gastric cancer cell under nonhypoxic condition whereas siRNA targeting MGr1-Ag showed a markedly decreased VCR-induced HIF-1alpha expression and transcriptional activity (P < 0.05). SiRNA targeting FAK or inhibitors of phosphatidylinositol 3-kinase (PI3K) and MAPK could inhibit VCR-induced HIF-1alpha expression, suggesting FAK-PI3K and p42/44MAPK (Erk1/2) may be the major signaling molecules in MGr1-Ag/37LRP-induced HIF-1alpha 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-1Alpha induction, thus revealing a novel aspect of HIF-1alpha regulation.
Liu
Lili
L
State Key Laboratory of Cancer Biology, Institute of Digestive Diseases Xijing Hospital, Fourth Military Medical University, Xi'an, PR China.
Ning
Xiaoxuan
X
Sun
Li
L
Shi
Yongquan
Y
Han
Shuang
S
Guo
Changcun
C
Chen
Yu
Y
Sun
Shiren
S
Yin
Fang
F
Wu
Kaichun
K
Fan
Daiming
D
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C470229:MGr1-antigen, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014750:Vincristine; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3