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.