Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p–HES1–AKT Pathway

Abstract

Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin infections and community-acquired pneumonia. However, there is accumulating evidence showing that tigecycline has anticancer properties. In this study, we found tigecycline could inhibit cell proliferation by inducing cell-cycle arrest, but not apoptosis in glioma. To find the underlying mechanism of how tigecycline inhibits cell proliferation, the expression of miRNAs, which were related to regulating cell-cycle progression, was detected with miRNA assay. We found that miR-199b-5p expression was significantly increased after tigecycline treatment, and miR-199b-5p target gene HES1 was downregulated. In addition, the PI3K/AKT pathway was inhibited and p21 expression was increased. When treated with tigecycline and miR-199b-5p antagomir simultaneously in glioma cells, we found that miR-199b-5p antagomir could partly block the effects induced by tigecycline. Tigecycline effectively upregulated miR-199b-5p expression and inhibited tumor growth in the xenograft tumor model of U87 glioma cells. These results suggest that tigecycline may induce cell-cycle arrest and inhibit glioma growth by regulating miRNA-199b-5p-HES1-AKT pathway. Thus, tigecycline is a promising agent in the treatment of malignant gliomas.

Inhibition of autophagy enhances the antitumour activity of tigecycline in multiple myeloma

“…As it has been reported that tigecycline impairs the cell viability mainly through inducing cell cycle arrest rather than apoptosis, we first analysed the effect of tigecycline on the cell cycle of MM cells and found that tigecycline treatment led to an increase in G0/G1 phase with diminished S phase (Figure A), suggesting that tigecycline is capable of inducing G0/G1 arrest to decelerate the cell cycle, and preventing the cells from entering the S phase and proliferating. As CDK2 is one of the key kinases controlling G1/S transition and DNA replication and p21 is a critical regulator of CDK2, we measured these two proteins and found that tigecycline markedly decreased the levels of CDK2 and p21 in three MM cell lines RPMI‐8226, NCI‐H929, and U266 (Figure B).…”

“…As it has been reported that tigecycline impairs the cell viability mainly through inducing cell cycle arrest rather than apoptosis, 11 we first analysed the effect of tigecycline on the cell cycle of MM cells and found that tigecycline treatment led to an increase in G0/G1 phase with diminished S phase (Figure 2A), suggesting that tigecycline is capable of inducing G0/G1 arrest to decelerate the cell cycle, and preventing the cells from entering the S phase and proliferating.…”

“…Beyond its role as an antimicrobial, accumulating evidence shows that tigecycline has anticancer properties. It can inhibit the growth and metastasis of multiple tumour cells, including acute myeloid leukaemia, gastric cancer, melanoma, neuroblastoma, cervical squamous cell carcinoma and glioma . The anticancer mechanism of tigecycline appears to vary in different tumour types.…”

“…It can inhibit the growth and metastasis of multiple tumour cells, including acute myeloid leukaemia, 6 gastric cancer, 7 melanoma, 8 neuroblastoma, 9 cervical squamous cell carcinoma 10 and glioma. 11 The anticancer mechanism of tigecycline appears to vary in different tumour types. Besides the inhibition of mitochondrial protein synthesis, other mechanisms including autophagy have been found to be involved in antitumour effects.…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…Further study demonstrated that after treating glioma U87 and U128 cells with TIG, the miRNA-199b-5p level obviously increased and the level of HES family BHLH transcription factor 1 (HES1), a target of miRNA-199b-5p, obviously decreased. Moreover, TIG decreased Akt phosphorylation at Ser473 and increased its target p21 level via the miRNA-199b-5p-HES1 axis (Yang et al, 2016). Another study showed that TIG could induce cell G1/S phase arrest and suppress migration/invasion by down-regulating the level of p21 in melanoma A375 and MV3 cell lines (Hu et al, 2016).…”