Insulin induces drug resistance in melanoma through activation of the PI3K/Akt pathway

Chi, Mengna, Ye, Yan, Zhang, Xu Dong and Chen, Jiezhong (2014) Insulin induces drug resistance in melanoma through activation of the PI3K/Akt pathway. Drug Design, Development and Therapy, 8 255-262. doi:10.2147/DDDT.S53568


Author Chi, Mengna
Ye, Yan
Zhang, Xu Dong
Chen, Jiezhong
Title Insulin induces drug resistance in melanoma through activation of the PI3K/Akt pathway
Journal name Drug Design, Development and Therapy   Check publisher's open access policy
ISSN 1177-8881
Publication date 2014-02-17
Year available 2014
Sub-type Article (original research)
DOI 10.2147/DDDT.S53568
Open Access Status DOI
Volume 8
Start page 255
End page 262
Total pages 8
Place of publication Macclesfield, United Kingdom
Publisher DOVE Medical Press
Collection year 2015
Language eng
Formatted abstract
Introduction: There is currently no curative treatment for melanoma once the disease spreads beyond the original site. Although activation of the PI3K/Akt pathway resulting from genetic mutations and epigenetic deregulation of its major regulators is known to cause resistance of melanoma to therapeutic agents, including the conventional chemotherapeutic drug dacarbazine and the Food and Drug Administration-approved mutant BRAF inhibitors vemurafenib and dabrafenib, the role of extracellular stimuli of the pathway, such as insulin, in drug resistance of melanoma remains less understood.

Objective: To investigate the effect of insulin on the response of melanoma cells to dacarbazine, and in particular, the effect of insulin on the response of melanoma cells carrying the BRAFV600E mutation to mutant BRAF inhibitors. An additional aim was to define the role of the PI3K/Akt pathway in the insulin-triggered drug resistance.

Methods: The effect of insulin on cytotoxicity induced by dacarbazine or the mutant BRAF inhibitor PLX4720 was tested by pre-incubation of melanoma cells with insulin. Cytotoxicity was determined by the MTS assay. The role of the PI3K/Akt pathway in the insulin-triggered drug resistance was examined using the PI3K inhibitor LY294002 and the PI3K and mammalian target of rapamycin dual inhibitor BEZ-235. Activation of the PI3K/Akt pathway was monitored by Western blot analysis of phosphorylated levels of Akt.

Results: Recombinant insulin attenuated dacarbazine-induced cytotoxicity in both wild-type BRAF and BRAFV600E melanoma cells, whereas it also reduced killing of BRAFV600E melanoma cells by PLX4720. Nevertheless, the protective effect of insulin was abolished by the PI3K and mTOR dual inhibitor BEZ-235 or the PI3K inhibitor LY294002.

Conclusion: Insulin attenuates the therapeutic efficacy of dacarbazine and PLX4720 in melanoma cells, which is mediated by activation of the PI3K/Akt pathway and can be overcome by PI3K inhibitors.
Keyword Insulin
PI3K/Akt
Melanoma
Drug resistance
DTIC
BRAF inhibitors
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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