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The siRNA-mediated downregulation of N-Ras sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors.

Abstract：

:The clinical benefit of selective BRAF inhibitor therapies is limited by the emergence of drug resistance. Here, we investigated the molecular basis underlying the acquired resistance to a BRAF inhibitor by comparing the signaling pathways in the parental A375P cells and the resistant subline (A375P/Mdr). We demonstrate that MAPK re-activation does not contribute to the mechanism of resistance to UAI-201 of A375P/Mdr cells. The relative quantitative analysis using the 2(-ΔΔCt) method revealed that the BRAF inhibitor resistance observed in A375P/Mdr cells is not mediated through the overexpression of MDR proteins. In particular, we found that the expression of N-Ras was upregulated in BRAF inhibitor-resistant A375P/Mdr cells compared with A375P cells. In fact, siRNA-mediated N-Ras knockdown partially conferred UAI-201 sensitivity to A375P/Mdr cells, implying that N-Ras upregulation confers acquired resistance to BRAF inhibition. Notably, the flow cytometric analysis of the N-Ras-knockdown A375P/Mdr cells revealed that UAI-201 causes a significant accumulation of cells in the G 0/G 1 phase with a concomitant decrease in the number of cells in the S and G 2/M phases. However, platelet-derived growth factor receptor β (PDGFRβ) knockdown failed to sensitize A375P/Mdr cells to growth suppression by UAI-201, although a remarkable increase in PDGFRβ was observed in the A375P cells after UAI-201 treatment. Taken together, our results suggest that N-Ras is worth targeting to improve the therapeutic outcome of melanomas with acquired resistance to BRAF inhibitors.

journal_name

Mol Cell Biochem

journal_title

Molecular and cellular biochemistry

authors

Ahn JH,Lee M

doi

10.1007/s11010-014-2034-2

subject

Has Abstract

pub_date

2014-07-01 00:00:00

pages

239-47

issue

1-2

eissn

0300-8177

issn

1573-4919

journal_volume

392

pub_type

杂志文章

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