title: GDC-0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway.
abstract: Angiopoietin-like protein 2 (ANGPTL2) plays an important role in inflammatory carcinogenesis and tumor metastasis. The compound GDC-0152 is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. However, the interaction between ANGPTL2 and GDC-0152 has not been studied. It has been proven that ANGPTL2 promotes metastasis of osteosarcoma. Therefore, in the present study, the effect of GDC-0152 on the malignant progression of osteosarcoma promoted by ANGPTL2 was investigated. Human osteosarcoma cell line SaOS2 cells were pre-treated or non-treated with GDC-0152 and then exposed to recombinant human ANGPTL2. The viability of SaOS2 cells was determined by MTT assay, the migration of SaOS2 cells was analyzed by chamber migration assay kit, and the SaOS2 cell apoptosis was determined by fluorescence-activated cell sorting (FACS) and nuclear staining. Treatment with ANGPTL2 increased SaOS2 cell growth and migration and decreased cell apoptosis. The increased cell growth and decreased cell apoptosis were significantly attenuated in SaOS2 cells receiving GDC-0152. However, the ANGPTL2-increased SaOS2 cell migration was not inhibited by GDC-0152 treatment. Furthermore, western blot analysis showed that the activation of phosphatidyl inositol 3-kinase (PI3K) (p85), PI3K (p110), protein kinase B (Akt) (Ser473), Akt (Thr308) and p38 mitogen-activated protein kinase (p38MAPK) were upregulated by ANGPTL2. Quantitative real-time polymerase chain reaction (qTR-PCR) and gelatin zymography showed that the mRNA expression and activity of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) were also increased by ANGPTL2. The upregulated activation of PI3K and Akt were significantly suppressed by the treatment of GDC-0152. In contrast, GDC-0152 did not suppress ANGPTL2-induced p38MAPK phosphorylation, MMP-9/MMP-2 mRNA expression or MMP-9/MMP-2 activity. Taken together, these data indicate that GDC-0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway. The present study indicated a novel therapeutic strategy to inhibit tumor growth by indirectly preventing ANGPTL2 signaling.
authors: Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Lin
authors: L
authors: Yang
authors: Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Taipengfei
authors: T
authors: Shu
authors: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Yingjian
authors: Y
authors: Liang
authors: Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Wenguang
authors: W
authors: Gu
authors: Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Chunlei
authors: C
authors: Wang
authors: Department of Emergency Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Xuanhe
authors: X
authors: Song
authors: Department of Emergency Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Changdong
authors: C
authors: Fan
authors: Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors: Wenbo
authors: W
authors: Wang
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D011758:Pyrroles; D011994:Recombinant Proteins; C579046:GDC-0152