Autophagy flux inhibition, G2/M cell cycle arrest and apoptosis induction by ubenimex in glioma cell lines
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Liping Han1,2,*, Yongfei Zhang3,*, Shuai Liu4,*, Qingwei Zhao2, Xianhong Liang2, Zhiguo Ma2, Prakash K. Gupta5, Miaoqing Zhao6 and Aihua Wang1
1Department of Neurology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, P.R. China
2Department of Neurology, Shandong Police Hospital, Jinan, P.R. China
3Department of Dermatology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, P.R. China
4Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China
5Certifying Scientist, Lab Solutions LLC, Atlanta, GA, USA
6Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China
*These authors contributed equally to this work
Aihua Wang, email: email@example.com
Keywords: glioma; ubenimex; G2/M phase arrest; autophagic flux; apoptosis
Received: August 24, 2017 Accepted: November 03, 2017 Published: November 21, 2017
This study aimed to investigate whether ubenimex could work as an anti-tumor drug alone in glioma cells and figure out the underlying potential mechanisms. Ubenimex is widely used as an adjunct therapy in multiple solid cancers. However, it is rarely used to treat glioblastoma. The function of ubenimex in enhancing JQ1 treatment sensitivity of glioma cells by blocking autophagic degradation of HEXIM1 was previously studied. However, the detailed mechanism of autophagy regulation by ubenimex remains unclear. The U87 and U251 cell lines were treated with different doses of ubenimex. Cell viability was measured by using the WST-8 assay. Cell death was assessed using trypan blue staining and flow cytometry. The migration and invasive ability of glioma cells were examined by transwell migration/invasion assay. LC3-GFP-RFP was used to measure autophagic flux. Protein expression was assessed by Western blot analysis. Autophagosomes were evaluated using the transmission electron microscopy. Moreover, cell cycle arrest (PI Staining) was measured by flow cytometry. Results revealed that ubenimex inhibited cell proliferation as well as migration/invasion in glioma cells. Besides, ubenimex increased glioma cell death via autophagic flux inhibition. Meanwhile, ubenimex induced G2/M phase arrest and apoptosis, and this effect was accompanied by the decreased levels of p-Akt, indicating the role of ubenimex in the regulation of glioma cell proliferation and metastasis. To sum up, this study concluded that ubenimex could work as an anti-tumor drug alone in the glioma cells via inhibiting autophagic flux and inducing G2/M arrest as well as apoptosis.
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