Targeting miR-21 Induces Autophagy and Chemosensitivity of Leukemia Cells

Abstract

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.

MicroRNA‐21 protects against cardiac hypoxia/reoxygenation injury by inhibiting excessive autophagy in H9c2 cells via the Akt/mTOR pathway

“…Seca et al . showed that treatment with an anti‐miR‐21 antibody induces an increase in the levels of the autophagy‐related proteins Beclin‐1, Vps34 and LC3‐II by decreasing Bcl‐2 expression 39. Our results also showed a negative interaction between Bcl‐2 and autophagic activity.…”

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

“…45 However, miR-21 downregulation causes enhanced autophagic activity and increased chemosensitivity to etoposide or doxorubicin in K562 and KYO-1 cells, and this chemosensitivity was reverted by pre-treating cells with autophagy inhibitor 3-MA. 46 Inhibition of miR-25 leads to autophagic cell death and increases chemosensitivity to isoliquiritigenin in MCF-7/ADR cells. 47 Considering the paradoxical role of autophagy in cancer therapy, recognizing functional autophagy status in tumors will be required to direct the appropriate therapy.…”

MicroRNA-30b Regulates High Phosphorus Level-Induced Autophagy in Vascular Smooth Muscle Cells by Targeting BECN1

“…Upregulation of miR-18a expression promotes autophagy in triple-negative cancer cells by suppressing the mTOR signaling pathway [16]. Seca et al showed that inhibition of miR-21 induced autophagy and chemosensitivity in leukemia cells [17]. Another study suggested that miR-23a-regulated autophagy is an important regulator of ultraviolet radiation-induced premature senescence in fibroblasts [18].…”