Let-7a microRNA modulates caspase-3-dependent apoptosis in melanoma cells treated with dabrafenib and trametinib combination.

IF 1.7 4区 医学 Q2 MEDICINE, GENERAL & INTERNAL
Murat Keser, Harika Atmaca
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引用次数: 0

Abstract

Background: Malignant melanoma is an aggressive tumor with high resistance to therapy. The emergence of RAS-driven secondary cancers and BRAF-inhibitor resistance has led to the development of combination therapies targeting both BRAF and MEK.

Aims: This study explored the mechanisms underlying the synergistic effects of dabrafenib (DAB) and trametinib (TM) in drug-resistant A375 and RPMI 7951 melanoma cells.

Methods: Cytotoxicity was assessed via MTT assay and combination effects were evaluated via combination index analysis. Apoptosis was analyzed by DNA fragmentation ELISA, while ectopic let-7a miRNA expression and inhibition were performed using lipofection. Gene expression levels were quantified by qRT-PCR, and protein expression was assessed via Western blot.

Results: The combination of 0.7 μM DAB and 5.0 μM TM exhibited synergistic cytotoxicity by inhibiting the pERK1/2 signaling pathway and inducing MITF expression. This resulted in mitochondria-mediated apoptosis, characterized by a decrease in anti-apoptotic Bcl-2 and an increase in pro-apoptotic Bax, caspase-9, and caspase-3 levels. Additionally, Let-7a was identified as a crucial regulator of apoptosis sensitivity by targeting caspase-3, the key executor of apoptosis.

Conclusions: These findings provide new insights into overcoming melanoma drug resistance through combined BRAF/MEK inhibition.

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来源期刊
Irish Journal of Medical Science
Irish Journal of Medical Science 医学-医学:内科
CiteScore
3.70
自引率
4.80%
发文量
357
审稿时长
4-8 weeks
期刊介绍: The Irish Journal of Medical Science is the official organ of the Royal Academy of Medicine in Ireland. Established in 1832, this quarterly journal is a contribution to medical science and an ideal forum for the younger medical/scientific professional to enter world literature and an ideal launching platform now, as in the past, for many a young research worker. The primary role of both the Academy and IJMS is that of providing a forum for the exchange of scientific information and to promote academic discussion, so essential to scientific progress.
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