The development of multidrug resistance (MDR) remains a major limitation to successful chemotherapy in osteosarcoma. Preventing the introduction of MDR has been a research hotspot in clinical and investigational oncology. The aim of this study was to evaluate the preventive effects of tetrandrine (TET) against MDR in osteosarcoma. For this purpose, U-2OS human osteosarcoma cells were treated with paclitaxel alone or a combination of paclitaxel with TET. The cells treated with paclitaxel alone eventually acquired MDR along with the overexpression of and highly activated P-glycoprotein (Pgp), while the cells treated with the paclitaxel-TET combination were sensitive to chemotherapeutic drugs and expressed decreased levels of Pgp and less Pgp activity. The promoter activities of MDR gene 1 (MDR1) and nuclear factor (NF)‑κB, and the expression levels of NF-κB and p-IκB-α were all enhanced in the cells cultured with paclitaxel alone. NF-κB DNA-binding activity and the binding ability of NF-κB to the MDR1 promoter were also enhanced in the cells cultured with paclitaxel alone compared to the control cells. However, the expression and activity of NF-κB were significantly decreased in the paclitaxel-TET combination-treated group as compared with the cells treated with paclitaxel alone. On the whole, our findings suggest that TET prevents paclitaxel-induced MDR by inhibiting Pgp overexpression through a mechanism that may involve the inhibition of NF-κB signaling in osteosarcoma.

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Chondrosarcoma (CHS) is the second most common malignant bone sarcoma with increased risk of invasion and metastasis. However, the regulatory mechanisms of CHS tumorigenesis remain unknown. Here we investigated the novel role of miR-497 in regulating chondrosarcoma cell growth and cell cycle arrest. RT-PCR analysis showed that the expression of miR-497 is aberrantly downregulated in human chondrosarcoma samples and cells. After transfection with miR-497 mimic or antagomir, the proliferation and apoptosis of JJ012 and OUMS-27 chondrosarcoma cells were determined by CCK-8 assay and flow cytometric analysis, respectively. Results showed that the proliferation capacity of JJ012 and OUMS-27 cells was significantly decreased by miR-497 overexpression but increased by miR-497 repression. Apoptosis in both cell types was remarkably enhanced by miR-497 mimic but inhibited by miR-497 antagomir. By bioinformatics and luciferase reporter analysis, Cdc25A was proven to be a direct target of miR-497 in chondrosarcoma cells. Further studies indicated that miR-497 modulates the growth of chondrosarcoma cells by targeting Cdc25A, in which the cell cycle inhibitor p21 is involved through a p53-independent pathway. In conclusion, we demonstrated that miR-497 represents a potential tumor suppressor in human chondrosarcoma that regulates the growth of chondrosarcoma cells by targeting Cdc25A. This may provide a novel therapeutic target for chondrosarcoma.

Osteoarthritis (OA) is the leading degenerative joint disease and featured by articular cartilage destruction, where chondrocyte apoptosis plays a critical role. Semaphorin-3A (Sema3A) has been implicated in OA chondrocyte physiology. In this study we aimed to uncover how Sema3A signaling is regulated in chondrocytes and investigate its role in OA chondrocyte survival. Here, we report that Sema3A and its receptor neuropilin-1 (Nrp1) are synchronously upregulated in cartilage chondrocytes of knee OA patients. Their expressions in chondrocytes could be induced by the stimulation of proinflammatory cytokines IL-1β and TNF-α and subsequent transcriptional activation orchestrated by C/EBPβ. The resulting excessive Sema3A signaling promotes chondrocyte apoptosis through impairing PI3K/Akt prosurvival signaling. These findings indicate a regulatory mechanism and a proapoptotic function of aberrant Sema3A signaling in OA chondrocytes, and suggest that targeting Sema3A signaling might interfere OA pathogenesis.

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