title: Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel.
abstract: Although the microtubule-stabilizing agent paclitaxel has been widely used for treatment of several cancer types, particularly for the malignancies of epithelia origin, it only shows limited efficacy on hematological malignancies. Emerging roles of O-GlcNAcylation modification of proteins in various cancer types have implicated the key enzymes catalyzing this reversible modification as targets for cancer therapy. Here, we show that the highly selective O-GlcNAcase (OGA) inhibitor thiamet-G significantly sensitized human leukemia cell lines to paclitaxel, with an approximate 10-fold leftward shift of IC50. Knockdown of OGA by siRNAs or inhibition of OGA by thiamet-G did not influence the cell viability. Furthermore, we demonstrated that thiamet-G binds to OGA in competition with 4-methylumbelliferyl N-acetyl-β-d-glucosaminide dehydrate, an analogue of O-GlcNAc UDP, thereby suppressing the activity of OGA. Importantly, inhibition of OGA by thiamet-G decreased the phosphorylation of microtubule-associated protein Tau and caused alterations of microtubule network in cells. It is noteworthy that paclitaxel combined with thiamet-G resulted in more profound perturbations on microtubule stability than did either one alone, which may implicate the underlying mechanism of thiamet-G-mediated sensitization of leukemia cells to paclitaxel. These findings thus suggest that a regimen of paclitaxel combined with OGA inhibitor might be more effective for the treatment of human leukemia.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Ping
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Feng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: songyuqin622@163.com.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Song
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: zhu-jun@bjcancer.org.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
mesh_terms: D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011714:Pyrans / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D011714:Pyrans; D013844:Thiazoles; D016875:tau Proteins; C572247:thiamet G; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D017239:Paclitaxel
keywords: Leukemia; Microtubule; O-GlcNAcase; Paclitaxel; Thiamet-G