Targeting miR-21 Induces Autophagy and Chemosensitivity of Leukemia Cells

• Tipo: Artigo em Revista Científica Internacional
• Data: 2013

Autores

Hugo Seca (Autor) Outra; Raquel T Lima (Autor) Outra; Vanessa Lopes Rodrigues (Autor) Outra; Jose E Guimaraes (Autor) FMUP; Gabriela M Almeida (Autor) Outra; Helena Vasconcelos, MH (Autor) FFUP

Revista

Título: Current Drug Targets

Vol. 14

Páginas: 1135-1143

ISSN: 1389-4501

Editora: Bentham Science

Indexação

ISI Web of Knowledge - 82 Citações

Scopus - 84 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-006-7ZY

DOI: 10.2174/13894501113149990185

Abstract (EN): Overexpression of oncomiR-21 has been observed in most cancer types, such as leukemia. This miR has been implicated in a number of cellular processes, including chemoresistance, possibly by directly modulating the expression of several apoptotic related proteins. It was recently shown to directly target Bcl-2 mRNA and upregulate Bcl-2 protein expression. Nevertheless, the possible effect of miR-21 in autophagy has never been addressed. This study investigates the effects of targeting miR-21 with antimiRs on chronic myeloid leukemia cellular autophagy and on associated drug sensitivity. We observed that miR-21 downregulation decreased cellular viability and proliferation, although no changes to the normal cell cycle profile were observed. miR-21 downregulation also caused increased programmed cell death and a decrease in the expression levels of Bcl-2 protein, although PARP cleavage was not affected, indicating that apoptosis was not the relevant mechanism underlying the observed results. Treatment with antimiR-21 caused an increase in the autophagy related proteins Beclin-1, Vps34 and LC3-II. Accordingly, autophagic vacuoles were visualized both by monodansylcadaverine (MDC) and acridine orange (AO) staining and also by transmission electron microscopy (TEM). Additionally, miR-21 downregulation increased K562 and KYO-1 cellular sensitivity to etoposide or doxorubicin. This chemosensitivity was reverted by pre-treating cells with 3-MA, an autophagy inhibitor. Finally, serum starvation (an autophagy inducer) also increased sensitivity to these drugs, confirming that autophagy sensitized these cells to the effect of these drugs. To the best of our knowledge, this is the first description of autophagy induction via miR-21 targeting and its involvement in drug sensitivity.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 9