共同抑制mTORC2和HSP90对白血病细胞的杀伤作用

Constitutive activation of the kinases AKT or PKC in blood cancers promotes tumor cell proliferation and survival and is associated with poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) and HSP90 work together to maintain the stability of AKT and classical (c)PKC (PKCα & PKCβ) proteins. We have showed that treating mouse leukemia cells with the mTOR inhibitor plus HSP90 inhibitor impaired AKT and cPKC protein stability. Consequently, we observed the anti-leukemia effects in both vitro and vivo experiments on our mouse model. This time we will investigate the stability of AKT and cPKC after treat human leukemia cells with mTOR inhibitor plus HSP90 inhibitor, we will also test whether the treatment promote human leukemia cells death. Hopefully these studies provide a mechanistic and clinical rationale to combine mTOR inhibitors with chaperone protein inhibitors to treat human blood cancers.

激酶AKT或者PKC的持续激活可促进血液肿瘤的增殖存活，并且和病人的低生存率密切相关,当前的热点集中在对AKT激酶活性抑制剂的研究中.而我们则发现哺乳动物雷帕霉素靶复合物2（mTORC2）能与分子伴侣热休克蛋白90协同作用来维持AKT和PKC蛋白质的维定性。在以前的研究中我们发现，在小鼠白血病细胞中能够通过抑制mTORC2和HSP90的功能来抑制AKT蛋白质的表达，并在体外及体内实验中均能很好地抑制小鼠白血病细胞的生长。本项目将以人白血病细胞株作为实验对象，通过药物抑制mTORC2和HSP90的活性，继而观察mTORC2抑制剂和HSP90抑制剂在人白血病细胞株中对蛋白质AKT及PKC的影响，并评估对人白血病细胞存活的影响，希望此项研究为临床上联合使用mTOR的抑制剂和热休克蛋白抑制剂治疗血液系统肿瘤提供了理论上的依据。