Shi Yijiang, Gera Joseph, Hu Liping, Hsu Jung-hsin, Bookstein Robert, Li Weiqun, Lichtenstein Alan
Division of Hematology-Oncology, West Los Angeles VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, Los Angeles, California 90073, USA.
Cancer Res. 2002 Sep 1;62(17):5027-34.
Recent work identifies the AKT kinase as a potential mediator of tumor expansion in multiple myeloma. The finding of PTEN mutations in several myeloma cell lines suggests that loss of PTEN function may be one mechanism by which AKT activity is increased in this disease. Because PTEN-deficient myeloma cells may have up-regulated activity of the mammalian target of rapamycin (mTOR), downstream of AKT, they may be particularly sensitive to mTOR inhibition. To test this hypothesis, we challenged myeloma cell lines with CCI-779, a newly developed analogue of rapamycin and an efficient inhibitor of mTOR. Three of four PTEN-deficient cell lines with constitutively active AKT were remarkably sensitive to cytoreduction and G(1) arrest induced by CCI-779 with ID(50) concentrations of <1 nM. In contrast, myeloma cells expressing wild-type PTEN were >1000-fold more resistant. Acute expression of a constitutively active AKT gene in CCI-779-resistant myeloma cells containing wild-type PTEN and quiescent AKT did not convert them to the CCI-779-sensitive phenotype. Conversely, expression of wild-type PTEN in CCI-779-sensitive, PTEN-deficient myeloma cells did not induce resistance. Differential sensitivity did not appear to be due to differences in the ability of CCI-779 to inhibit mTOR and induce dephosphorylation of p70S6kinase or 4E-BP1. However, CCI-779 inhibited expression of c-myc in CCI-sensitive PTEN-null myeloma cells but had no effect on expression in CCI-resistant cells. In contrast, cyclin D1 expression was not altered in either sensitive or resistant cells. These results indicate that PTEN-deficient myeloma cells are remarkably sensitive to mTOR inhibition. Although the results of transfection studies suggest that the level of PTEN and AKT function per se does not regulate sensitivity, PTEN/AKT status may be a good predictive marker of sensitivity.
近期研究确定AKT激酶是多发性骨髓瘤肿瘤增殖的潜在介导因子。在多个骨髓瘤细胞系中发现PTEN突变，提示PTEN功能缺失可能是该疾病中AKT活性增加的一种机制。由于PTEN缺陷的骨髓瘤细胞可能使雷帕霉素哺乳动物靶蛋白（mTOR）的活性上调，mTOR是AKT的下游分子，因此它们可能对mTOR抑制特别敏感。为验证这一假说，我们用CCI-779（一种新开发的雷帕霉素类似物及有效的mTOR抑制剂）处理骨髓瘤细胞系。四个PTEN缺陷且AKT持续激活的细胞系中，有三个对CCI-779诱导的细胞数量减少和G(1)期阻滞极为敏感，其半数抑制浓度（ID(50)）<1 nM。相反，表达野生型PTEN的骨髓瘤细胞的耐药性要强1000倍以上。在含有野生型PTEN且AKT静止的对CCI-779耐药的骨髓瘤细胞中急性表达持续激活的AKT基因，并未使其转变为对CCI-779敏感的表型。相反，在对CCI-779敏感、PTEN缺陷的骨髓瘤细胞中表达野生型PTEN，并未诱导耐药性产生。差异敏感性似乎并非由于CCI-779抑制mTOR及诱导p70S6激酶或4E-BP1去磷酸化的能力不同所致。然而，CCI-779抑制了对CCI敏感的PTEN缺失骨髓瘤细胞中c-myc的表达，但对耐药细胞中的表达无影响。相反，细胞周期蛋白D1的表达在敏感或耐药细胞中均未改变。这些结果表明，PTEN缺陷的骨髓瘤细胞对mTOR抑制极为敏感。虽然转染研究结果提示PTEN水平和AKT功能本身并不调节敏感性，但PTEN/AKT状态可能是敏感性的良好预测指标。
