Endothelial Monocyte-Activating Polypeptide-II Induces BNIP3-Mediated Mitophagy to Enhance Temozolomide Cytotoxicity of Glioma Stem Cells via Down-Regulating MiR-24-3p

Abstract

Preliminary studies have shown that endothelial-monocyte-activating polypeptide-II (EMAP-II) and temozolomide (TMZ) alone can exert cytotoxic effects on glioma cells. This study explored whether EMAP-II can enhance the cytotoxic effects of TMZ on glioma stem cells (GSCs) and the possible mechanisms associated with Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy facilitated by miR-24-3p regulation. The combination of TMZ and EMAP-II significantly inhibited GSCs viability, migration, and invasion, resulting in upregulation of the autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I but down-regulation of the proteins P62, TOMM 20 and CYPD, changes indicative of the occurrence of mitophagy. BNIP3 expression increased significantly in GSCs after treatment with the combination of TMZ and EMAP-II. BNIP3 overexpression strengthened the cytotoxic effects of EMAP-II and TMZ by inducing mitophagy. The combination of EMAP-II and TMZ decreased the expression of miR-24-3p, whose target gene was BNIP3. MiR-24-3p inhibited mitophagy and promoted proliferation, migration and invasion by down-regulating BNIP3 in GSCs. Furthermore, nude mice subjected to miR-24-3p silencing combined with EMAP-II and TMZ treatment displayed the smallest tumors and the longest survival rate. According to the above results, we concluded that EMAP-II enhanced the cytotoxic effects of TMZ on GSCs' proliferation, migration and invasion both in vitro and in vivo.

Autophagy as a Potential Therapy for Malignant Glioma

“…A downregulation of miR-24-3p by administering GSC (U-87 and U-251 cells) with a combined treatment of TMZ plus the endothelial-monocyte-activating polypeptide-II (EMAPII), a secretory polypeptide with anticancer properties, led to an overexpression of BNIP3, which induced mitophagy. TMZ plus EMAP-II showed a synergistical effect, increasing the sensitivity of tumor cells to TMZ, reducing GSC viability, migration, and invasion [219].…”

Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer

“…Interestingly, low-dose EMAP II induced Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy by downregulating miR-24-3p, thereby enhancing the temozolomide cytotoxicity of GSCs 103 . Mice treated simultaneously with EMAP II, temozolomide and miR-24-3p inhibitor showed the smallest tumors and the longest survival rates, suggesting that the combined use of EMAP II and temozolomide might be a new approach for the treatment of glioma.…”

Advances in circular RNAs and their role in glioma (Review)

“…The binding of EMAP-II to temozolomide (TMZ) reduces the expression of miR-24-3p, thereby enhancing the cytotoxic effect of TMZ on the proliferation, migration and invasion of germline stem cells in vitro and in vivo, further enhancing its therapeutic efficacy. circRNAs play important roles in the regulation of this process (68). Combined treatment with miR-24-3p (-), EMAP-II and TMZ can reduce tumour malignancy and increase the survival rate, whereas it has also been reported that EMAP-II can promote tumour necrosis factor receptor 1 apoptosis, thereby exerting an antitumour effect (68).…”

“…circRNAs play important roles in the regulation of this process (68). Combined treatment with miR-24-3p (-), EMAP-II and TMZ can reduce tumour malignancy and increase the survival rate, whereas it has also been reported that EMAP-II can promote tumour necrosis factor receptor 1 apoptosis, thereby exerting an antitumour effect (68). In addition, the permeability of the blood-brain barrier is increased to further promote tumour cell apoptosis.…”