Lonidamine (LND), a metabolic modulator, sensitizes DB-1 human melanoma to doxorubicin (DOX) chemotherapy by acidifying and de-energizing the tumor.,This report compares the effects of LND on two human melanoma lines, DB-1 and WM983B, which exhibit different metabolic properties.,Using liquid chromatography mass spectrometry and Seahorse analysis, we show that DB-1 was more glycolytic than WM983B in vitro.,31P magnetic resonance spectroscopy (MRS) indicates that LND (100 mg/kg, i.p.) induces similar selective acidification and de-energization of WM983B xenografts in immunosuppressed mice.,Over three hours, intracellular pH (pHi) of WM983B decreased from 6.91 ± 0.03 to 6.59 ± 0.10 (p = 0.03), whereas extracellular pH (pHe) of this tumor changed from 7.03 ± 0.05 to 6.89 ± 0.06 (p = 0.19).,A decline in bioenergetics (β-NTP/Pi) of 55 ± 5.0% (p = 0.03) accompanied the decline in pHi of WM983B.,Using 1H MRS with a selective multiquantum pulse sequence and Hadamard localization, we show that LND induced a significant increase in tumor lactate levels (p < 0.01).,LND pre-treatment followed by DOX (10 mg/kg, i.v.) produced a growth delay of 13.7 days in WM983B (p < 0.01 versus control), a growth delay significantly smaller than the 25.4 days that occurred with DB-1 (p = 0.03 versus WM983B).,Differences in relative levels of glycolysis may produce differential therapeutic responses of DB-1 and WM983B melanomas.
The glucose transporter isoform 1 (GLUT1; SLC2A1) is a key rate-limiting factor in the transport of glucose into cancer cells.,Enhanced GLUT1 expression and accelerated glycolysis have been found to promote aggressive growth in a range of tumor entities.,However, it was unknown whether GLUT1 directly impacts metastasis.,Here, we aimed at analyzing the expression and function of GLUT1 in malignant melanoma.,Immunohistochemical analysis of 78 primary human melanomas on a tissue micro array showed that GLUT1 expression significantly correlated with the mitotic activity and a poor survival.,To determine the functional role of GLUT1 in melanoma, we stably suppressed GLUT1 in the murine melanoma cell line B16 with shRNA.,GLUT1 suppressed melanoma cells revealed significantly reduced proliferation, apoptosis resistance, migratory activity and matrix metalloproteinase 2 (MMP2) expression.,In a syngeneic murine model of hepatic metastasis, GLUT1-suppressed cells formed significantly less metastases and showed increased apoptosis compared to metastases formed by control cells.,Treatment of four different human melanoma cell lines with a pharmacological GLUT1 inhibitor caused a dose-dependent reduction of proliferation, apoptosis resistance, migratory activity and MMP2 expression.,Analysis of MAPK signal pathways showed that GLUT1 inhibition significantly decreased JNK activation, which regulates a wide range of targets in the metastatic cascade.,In summary, our study provides functional evidence that enhanced GLUT1 expression in melanoma cells favors their metastatic behavior.,These findings specify GLUT1 as an attractive therapeutic target and prognostic marker for this highly aggressive tumor.