Background: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Meteorin-like (metrnl) is a recently identified adipomyokine that beneficially affects glucose metabolism; however, its underlying mechanism of action is not completely understood. We here show that the level of metrnl increases in vitro under electrical pulse stimulation and in vivo in exercised mice, suggesting that metrnl is secreted during muscle contractions. In addition, metrnl increases glucose uptake via the calcium-dependent AMPKa2 pathway in skeletal muscle cells and increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPKa2dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. An intraperitoneal injection of recombinant metrnl improved glucose tolerance in mice with high-fat-diet-induced obesity or type 2 diabetes, but not in AMPK b1b2 muscle-specific null mice. Metrnl improves glucose metabolism via AMPKa2 and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.Abbreviations ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; BAPTA-AM, 1,2-Bis (2-aminophenoxy) ethane-N,N,N 0 ,N 0 -tetraacetic acid tetrakis (acetoxymethyl ester; EPS, electrical pulse stimulation; GLUT4, glucose transporter type 4; GST, glutathione S-transferase; GTT, glucose tolerance test; HDAC5, histone deacetylase 5; HFD, high-fat diet; ICC, immunocytochemistry; MAPK, mitogen-activated protein kinase; TBC1D1, TBC1 domain family member 1.

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Laminarin is a component of brown seaweed, especially isolated from Salicornia herbacea. Laminarin was known to have various physiological functions, however, the molecular mechanism is still unclear. In this study, we report that laminarin stimulates an activation of AMP-activated protein kinase (AMPK) and increases glucose uptake in rat L6 myotubes. Laminarin also increases an intracellular calcium release. Inhibition of Ca2+ release, using with CaMKK inhibitor, STO-609, blocked laminarin-induced AMPK activity, indicating that laminarin stimulated AMPK activity via calcium. In addition, laminarin activates p38 mitogen-activated protein kinase (MAPK) signaling pathways depending on AMPK activity. Moreover, the inhibition of either AMPK or p38 MAPK blocked laminarin-induced glucose uptake in rat L6 myotubes. Taken together, these results demonstrate that the hypoglycemic effect of laminarin is caused by its ability to activate AMPK-p38 MAPK pathways in skeletal muscles.