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Fangchinoline suppresses the proliferation, invasion and tumorigenesis of human osteosarcoma cells through the inhibition of PI3K and downstream signaling pathways.

ABSTRACT: Osteosarcoma is the most common malignant bone tumor. Most patients diagnosed with osteosarcoma are less than 20 years of age. Osteosarcoma cells proliferate rapidly and invade other tissues. At present, neoadjuvant chemotherapy is the primary pharmacodynamic strategy to prevent the progression of osteosarcoma. However, adverse effects of this strategy limit its long‑term application. Previous research has shown that fangchinoline exerts antitumor effects on several types of tumor cells; however, its effect on osteosarcoma cells remains unknown. The present study evaluated the effects of fangchinoline on the proliferation, apoptosis, migration and invasion of osteosarcoma cells in vitro and on their tumorigenesis in vivo and determined the possible underlying mechanism of action. Fangchinoline‑treated MG63 and U20S cells showed significantly decreased proliferation and significantly increased apoptosis. Fangchinoline markedly suppressed the migration and invasion of the MG63 cells. Fangchinoline‑treated MG63 cells showed significantly decreased expression of phosphoinositide 3‑kinase (PI3K) and Aktp‑Thr308. Moreover, fangchinoline‑treated MG63 cells showed downregulated expression of cyclin D1 and matrix metalloproteinase 2 and 9, which act downstream of PI3K, and upregulated expression of caspase‑3 and caspase‑8. Furthermore, fangchinoline suppressed the growth of subcutaneous osteosarcoma tumors in Balb/c mice subcutaneously injected with osteosarcoma cells. These findings suggest that fangchinoline inhibits the progression of osteosarcoma by suppressing the proliferation, migration and invasion and by accelerating the apoptosis of osteosarcoma cells. In addition, our results suggest that the mechanism underlying the antitumor effects of fangchinoline involve the inhibition of PI3K and its downstream signaling pathways.

SUBMITTER: Li X

PROVIDER: S-EPMC5504998 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:Honokiol (HNK) is a small biphenolic compound, which exerts antineoplastic effects in various types of cancer. However, the mechanism underlying the antitumor effects of HNK in osteosarcoma (OS) cells is not yet fully understood. Emerging evidence has indicated that microRNAs (miRNAs/miRs) serve key roles in numerous pathological processes, including cancer. It has previously been reported that Chinese medicinal herbs harbor anticancer properties via modulating miRNA expression. Therefore, the present study aimed to determine whether HNK could suppress OS cell growth by regulating miRNA expression. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis were used to evaluate the cell proliferation and apoptosis in human OS cells after treatment with HNK, respectively. The results demonstrated that HNK inhibits proliferation and induces apoptosis of human OS cells in a dose?dependent manner. Furthermore, HNK?induced apoptosis was characterized by upregulation of proapoptotic proteins, including cleaved?caspase?3, cleaved?poly (ADP?ribose) polymerase and B?cell lymphoma 2 (Bcl?2)?associated X protein, and downregulation of the anti?apoptotic protein Bcl?2. Reverse transcription?quantitative polymerase chain reaction (RT?qPCR) verified that HNK was able to induce aberrant expression of miRNAs in human OS cells, and miR?21 was one of the miRNAs that was most significantly downregulated. To further investigate miR?21 function, the present study validated that HNK reduces miR?21 levels in a dose?dependent manner. In addition, restoration of miR?21 expression abrogated the suppressive effects of HNK on OS cells. Luciferase assay and western blot analysis identified that miR?21 inhibits the expression of phosphatase and tensin homolog (PTEN) by directly targeting its 3'-UTR. Notably, HNK was able to suppress the phosphoinositide 3?kinase (PI3K)/protein kinase B (AKT) signaling pathway; however, it was reactivated by miR?21 overexpression. Taken together, these data indicated that HNK may inhibit proliferation and induce apoptosis of human OS cells by modulating the miR?21/PTEN/PI3K/AKT signaling pathway. Therefore, miR?21 may be considered a potential therapeutic target for the treatment of osteosarcoma with HNK.

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Fangchinoline suppresses the proliferation, invasion and tumorigenesis of human osteosarcoma cells through the inhibition of PI3K and downstream signaling pathways.

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