Melanoma is an aggressive form of skin cancer characterized by rapid invasion and metastasis.,CD147 is known to be functioning in cell invasion.,In this study, we showed that CD147 was translocated from the cell membrane to the mitochondria in advanced melanoma.,Melanoma patients with CD147 localized to the mitochondria confer a worse prognosis.,The mitochondrial CD147 levels are correlated with the invasion potential of various melanoma cell lines as well as mitochondrial energy metabolism.,Depletion of CD147 decreased the activity of mitochondrial complex V.,STRING analysis for protein-protein interaction networks (PPIN) in CD147-depleted melanoma cells showed that mitochondrial proteins HSP60 and ATP5B, a subunit of mitochondrial complex V, were node proteins.,HSP60 upregulation was correlated with a worse prognosis of melanoma patients.,Co-immunoprecipitation (Co-IP) assay indicates that CD147 interacts with HSP60.,These data suggested that mitochondrial CD147 may prompt HSP60 to activate ATP5B, thereby promoting the mitochondrial aerobic oxidation and the invasive abilities of melanoma cells.,Correlation analysis of the data acquired from patients was helpful to draw a 5-year survival curve for patients who screened positive and negative for mitochondrial CD147.,This study unravels the function of CD147 in tumor invasion and highlights it as a potential tumor therapeutic target.
Metformin is one of the biguanides commonly used in patients with type II Diabetes Mellitus.,Apart from its hypoglycemic properties, metformin also inhibits the cell cycle by restricting protein synthesis and cell proliferation via regulating the LKB1/AMPL pathway.,Furthermore, it also enhances the PD-1 blockade through a reduction of tumor hypoxia.,Metformin has shown a significant favorable impact on treatment-related outcomes in solid tumors, but these outcomes have not been replicated in the limited clinical studies done on malignant melanoma.,Moreover, none of these studies have reported on the efficacy of the combined use of metformin and immune checkpoint inhibitors (ICIs).,This is a retrospective cohort study that includes patients diagnosed with metastatic malignant melanoma and treated with ipilimumab, nivolumab, and/or pembrolizumab (Cohort A); or ipilimumab, nivolumab, and/or pembrolizumab plus metformin (Cohort B) between January 1st 2011 through December 15th 2017.,In this study, patients are stratified based on anti-PD-1 only and anti-CTLA4/anti-PD-1 combination therapies in each cohort.,Objective response rate (ORR) is the primary endpoint.,Disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) are the secondary endpoints.,Cohort A had 33 patients (60%), while cohort B had 22 (40%).,Overall patient characteristics were similar between both cohorts.,ORR was higher in cohort B (68.2% vs.,54.5%, P = 0.31).,The DCR was higher in cohort B as well (77.3% vs.,60.6%, P = 0.19).,Median OS (46.7 months vs. 28 months), and median PFS (19.8 months vs. 5 months) were longer in cohort B.,However, on univariate and multivariate analyses, none of these differences were statistically significant.,The mean number of new metastatic sites which appeared during therapy were significantly higher in cohort A (A:1.51 vs.,B:0.59, P = 0.009).,We have observed favorable treatment-related outcomes (ORR, DCR, median PFS and median OS) in patients who have received metformin in combination with ICIs without reaching significance, probably, due to small sample size.,Hence, large prospective clinical trials are required to study the synergistic effect of metformin in combination with ICIs before it can be recommended as routine additive therapy.