title: Inhibition of mTOR pathway sensitizes acute myeloid leukemia cells to aurora inhibitors by suppression of glycolytic metabolism.
abstract: Aurora kinases are overexpressed in large numbers of tumors and considered as potential therapeutic targets. In this study, we found that the Aurora kinases inhibitors MK-0457 (MK) and ZM447439 (ZM) induced polyploidization in acute myeloid leukemia (AML) cell lines. The level of glycolytic metabolism was significantly increased in the polyploidy cells, which were sensitive to glycolysis inhibitor 2-deoxy-D-glucose (2DG), suggesting that polyploidy cells might be eliminated by metabolism deprivation. Indeed, inhibition of mTOR pathway by mTOR inhibitors (rapamycin and PP242) or 2DG promoted not only apoptosis but also autophagy in the polyploidy cells induced by Aurora inhibitors. Mechanically, PP242 or2DGdecreased the level of glucose uptake and lactate production in polyploidy cells as well as the expression of p62/SQSTM1. Moreover, knockdown of p62/SQSTM1 sensitized cells to the Aurora inhibitor whereas overexpression of p62/SQSTM1 reduced drug efficacy. Thus, our results revealed that inhibition of mTOR pathway decreased the glycolytic metabolism of the polyploidy cells, and increased the efficacy of Aurora kinases inhibitors, providing a novel approach of combination treatment in AML.
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou 510630, China. liuq9@mail.sysu.edu.cn.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Liu
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Le-Xun
authors.initials: LX
authors.lastname: Wang
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Fang
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Dong-Fan
authors.initials: DF
authors.lastname: Xu
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Chen
authors.forename: Shao-Wu
authors.initials: SW
authors.lastname: Wang
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011123:Polyploidy; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020298:U937 Cells; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D064127:Aurora Kinases; D001549:Benzamides; D003847:Deoxyglucose; D005947:Glucose; D007211:Indoles; D019344:Lactic Acid; D010879:Piperazines; D011687:Purines; D011799:Quinazolines; D000071456:Sequestosome-1 Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; C099718:SQSTM1 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C572919:PP242