Berberine Reduces the Metastasis of Chondrosarcoma by Modulating theαvβ3 Integrin and the PKCδ, c-Src, and AP-1 Signaling Pathways

Abstract

Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis, especially to the lungs. Patients diagnosed with chondrosarcoma have poor prognosis. Berberine, an active component of the Ranunculaceae and Papaveraceae families of plant, has been proven to induce tumor apoptosis and to prevent the metastasis of cancer cells. However, the effects of berberine in human chondrosarcoma are largely unknown. In this study, we found that berberine did not induce cell apoptosis in human primary chondrocytes and chondrosarcoma cells. However, at noncytotoxic concentrations, berberine reduced the migration and invasion of chondrosarcoma cancer cells. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. We also found that incubation of chondrosarcoma cells with berberine reduced mRNA transcription for, and cell surface expression of, the αvβ3 integrin, with additional inhibitory effects on PKCδ, c-Src, and NF-κB activation. Thus, berberine may be a novel antimetastasis agent for the treatment of metastatic chondrosarcoma.

The importance of Src signaling in sarcoma

“…The effect of Src on the metastasis of osteosarcoma cells is therefore controversial. A number of studies reported that inhibition of c-Src signaling was able to reduce metastasis of chondrosarcoma (57,58). Other studies found that Src inhibition could overcome chemoresistance to induce apoptosis and to inhibit migration (59).…”

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway

“…It means that NE takes no effect on PKA activation in MCF-7 cell. Given the important role of PKCδ in Src phosphorylation in malignant cells, [24,25] we employed PKCδ kinase activity kit to detect PKCδ activity in MCF-7 cells after treatment with NE and CAR. It showed in our study that PKCδ activity increased in MCF-7 cells treated by NE, and PKCδ siRNA or CAR could inhibit NE-mediated PKCδ activation, resulting in decreased Src S17 phosphorylation.…”

“…[22,23] Recent research showed that PKCδ played important role in Src phosphorylation in malignant cells. [24,25] So, we employed PKCδ kinase activity kit to detect PKCδ activity in MCF-7 cells treated by NE and CAR. Our data in this study documented that PKCδ activity increased in MCF-7 cells treated by NE (nearly two-fold), but CAR could inhibit PKCδ activity induced by NE [ Figure 6d].…”

Effects of Berberine and Its Derivatives on Cancer: A Systems Pharmacology Review

“…Berberine inhibits the release of MMP-2 from tumor cells and thus inhibits tumor cell destruction of the tissue matrix. Berberine increased the activities of numerous proteins involved in proliferation, such as Janus Kinase 2 (JAK2), Phosphoinositide 3-kinase (PI3K), activator protein-1 (AP-1), and NF-kappaB (Mahata et al, 2011;Fu et al, 2013;Wu et al, 2013;Belanova et al, 2019;El-Zeftawy et al, 2019;Jiang et al, 2019). These proteins decreased IL-8 expression in the TNBC cell line, MDA-MB-231.…”