mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival

详细信息    查看全文

• 作者：Yonghuai Feng^a ; ^b ; ^c ; ^d ; ¹ ; ^{yhfengpeking@126.com} ; Liusong Wu^e ; ¹
• 关键词：Acute myeloid leukemia ; mTOR ; PFKFB3
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2017
• 出版时间：5 February 2017
• 年：2017
• 卷：483
• 期：2
• 页码：897-903
• 全文大小：1447 K
• 卷排序：483

文摘

Although mTOR (mammalian target of rapamycin) activation is frequently observed in acute myeloid leukemia (AML) patients, the precise function and the downstream targets of mTOR are poorly understood. Here we revealed that PFKFB3, but not PFKFB1, PFKFB2 nor PFKFB4 was a novel downstream substrate of mTOR signaling pathway as PFKFB3 level was augmented after knocking down TSC2 in THP1 and OCI-AML3 cells. Importantly, PFKFB3 silencing suppressed glycolysis and cell proliferation of TSC2 silencing OCI-AML3 cells and activated apoptosis pathway. These results suggested that mTOR up-regulation of PFKFB3 was essential for AML cells survival. Mechanistically, Rapamycin treatment or Raptor knockdown reduced the expression of PFKFB3 in TSC2 knockdown cells, while Rictor silencing did not have such effect. Furthermore, we also revealed that mTORC1 up-regulated PFKFB3 was dependent on hypoxia-inducible factor 1α (HIF1α), a positive regulator of glycolysis. Moreover, PFKFB3 inhibitor PFK15 and rapamycin synergistically blunted the AML cell proliferation. Taken together, PFKFB3 was a promising drug target in AML patients harboring mTOR hyper-activation.