Dauricine inhibits proliferation and promotes death of melanoma cells via inhibition of Src/STAT3 signaling

Abstract

Melanoma is the most common type of skin cancer. Signal transducer and activator of transcription 3 (STAT3) signaling has been demonstrated to be a therapeutic target for melanoma. Dauricine (Dau), an alkaloid compound isolated from the root of Menispermum dauricum DC., has shown tumor-suppressing effects in multiple human cancers, but its potential in melanoma remains unexplored. In this study, we demonstrated that Dau significantly inhibited the viability and proliferation of A375 and A2058 melanoma cells. Death of melanoma cells was also markedly promoted by Dau. Moreover, Dau inhibited phosphorylation-mediated activation of STAT3 and Src in a dose-dependent manner. Notably, constitutive activation of Src partially abolished the antiproliferative and cytotoxic activities of Dau on melanoma cells.Molecular docking showed that Dau could dock on the kinase domain of Src with a binding energy of −10.42 kcal/mol. Molecular dynamics simulations showed that Src-Dau binding was stable. Surface plasmon resonance imaging analysis also showed that Dau has a strong binding affinity to Src. In addition, Dau suppressed the growth of melanoma cells and downregulated the activation of Src/STAT3 in a xenograft model in vivo. These data demonstrated that Dau inhibits proliferation and promotes cell death in melanoma cells by inhibiting the Src/STAT3 pathways.

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

“…Moreover, dauricine also inhibited PI3K/Akt signaling activation and exerted antitumor effects [ 174 ]. In addition, it inhibited melanoma cell proliferation and strongly induced melanoma cell death by inhibiting the phosphorylation and activation of the Src protein and the activation of downstream signals (e.g., STAT3 protein) [ 175 ]. Dauricine downregulated the expression of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2).…”

Current understanding of epigenetics role in melanoma treatment and resistance

“…It has been demonstrated that shikonin (a naphthoquinone pigment extracted from the dried root of Zicao ( Lithospermum erythrorhizon, Onosma paniculata, or Arnebia euchroma, as a traditional Chinese herbal medicine) could block the phosphorylation of STAT3, decrease the levels of STAT3-targeted genes involved in melanoma survival and migration (Mcl-1, Bcl-2, MMP-2), and finally suppress melanoma growth [ 51 , 52 ]. In a different study, the inhibition of the viability and proliferation of A375 and A2058 melanoma cells was shown by the dauricine via blocking the phosphorylation-mediated activation of STAT3 and Src in a dose-dependent manner [ 34 , 53 – 55 ]. Recently, Meng et al have also evaluated the potent anti-melanoma activity of podocarpusflavone A (PCFA).…”

Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics

“…Dauricine : Dauricine, an alkaloid compound isolated from the root of Menispermum dauricum , has been shown with tumor‐suppressing effects in multiple human cancers (Deng et al, 2021). Also, dauricine enhanced the sensitivities of hepatocellular carcinoma cells to chemotherapeutic reagents, including cisplatin, sorafenib, and isoliensinine.…”