Different effects of the inhibition of Src activity on Akt/PKB in melanoma cells with wild BRAF and mutated BRAF V600E

Zdena Tuháčková,Petra Žáková,Jiří Réda,Lubica Ondrušová

doi:10.4236/abc.2013.33a002

Abstract

Src regulates cell adhesion, invasiveness, motility and growth in cancer cells. In melanoma, accumulating data show that Src inhibition can be effective and may enhance the effects of other agents. Increased Src expression and activity thus has recently become a target for drug therapy. Several melanoma cell lines were exposed to inhibitors of Src activity despite their broad specificity. To examine the particular activity of Src in human melanoma cells, we used SU6656, the selective inhibitor of Src family protein kinases. The activity of Src and cell proliferation were suppressed in HBL human cells, wild type melanoma cells and in SK-MEL-5 human melanoma cells harboring mutant BRAF V600E, upon their treatment with SU6656. The suppression of Src kinase activity had not inhibitory effects on Akt/PKB activity in SK-MEL-5 cells, which we have previously found in HBL cells. This may indicate that changes of Src involvement in the control of Akt/PKB activity and its downstream signaling could be induced by BRAF V600E mutation in SK-MEL-5 cells.

Highlights

Acquired resistance that is often developed to targeted therapies, has become a great clinical problem and is currently in the center of intensive clinical and basic research
Several melanoma cell lines were exposed to inhibitors of Src activity despite their broad specificity
The activity of Src and cell proliferation were suppressed in HBL human cells, wild type melanoma cells and in SK-MEL-5 human melanoma cells harboring mutant BRAF V600E, upon their treatment with SU6656

Summary

Introduction

Acquired resistance that is often developed to targeted therapies, has become a great clinical problem and is currently in the center of intensive clinical and basic research. The inhibition of mTORC1 by rapamycin was shown to induce phosphorylation and activation of Akt/PKB and its downstream signaling in some cancer cells [1], indicating the induction of a negative feedback mechanism that may reduce the anti-tumor effects of mTOR inhibition and develop drug resistance [2]. Another efficient inhibitor, vemurafenib is a smallmolecule drug that inhibits BRAF [3] and achieves clinical responses in patients with Braf—mutant melanoma. Other BRAF inhibitors may induce invasion and cell proliferation through paradoxical activation of MAPK pathway in melanoma cells [5,6]

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