Krasil'nikov M A, Luzai E V, Scherbakov A M, Shatskaya V A, Shtil A A, Gershtein E S
Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia.
Biochemistry (Mosc). 2004 Mar;69(3):322-30. doi: 10.1023/b:biry.0000022065.17006.7d.
Phosphatidylinositol-3 kinase (PI3K) belongs to one of the most important cellular proteins involved in the transmission of anti-apoptotic signal and regulation of survival pathways in tumor cells. Earlier we have found that prolonged treatment of melanoma cells with dexamethasone results in formation of a cell subline which was resistant to growth inhibitory dexamethasone action. We showed that constitutive activation of PI3K can be considered as one of the factors that regulate cell resistance to dexamethasone. Here we demonstrate that increased level of PI3K protein in dexamethasone-resistant cells correlates with partial decrease in expression of down-stream target of PI3K--protein kinase B (PKB). Study of the cell's sensitivity to various damaging agents showed that the cells after prolonged dexamethasone treatment are characterized by increased level of the resistance to both hormonal drugs and hypoxia, and at the same time with high sensitivity to ultraviolet (UV) radiation or anti-tumor agents such as adriamycin. As revealed, hypoxic conditions or short-term dexamethasone treatment of the resistant cells lead to a substantial increase in the PKB level, whereas neither UV radiation nor adriamycin affects the PKB level in these cells. We demonstrate that long-term dexamethasone treatment of melanoma cells results in the accumulation of the active form of mitogen-transducing signaling protein STAT3 (Signal Transducer and Activator of Transcription-3), which also contributes to inducing the melanoma cell's resistance to antiproliferative action of dexamethasone. We suggest that decreased level of PKB in combination with an activation of PI3K/STAT3 signaling in the melanoma cells after prolonged dexamethasone treatment may be one of the mechanisms of different sensitivity of these cells to hormonal drugs and damaging agents. The model of the progression of hormonal resistance of in vitro cultured tumor cells is presented.
磷脂酰肌醇-3激酶（PI3K）属于参与抗凋亡信号传递和肿瘤细胞生存途径调节的最重要细胞蛋白之一。我们之前发现，用地塞米松长期处理黑色素瘤细胞会导致形成一个对生长抑制性地塞米松作用具有抗性的细胞亚系。我们表明，PI3K的组成性激活可被视为调节细胞对地塞米松抗性的因素之一。在此我们证明，地塞米松抗性细胞中PI3K蛋白水平的升高与PI3K下游靶点——蛋白激酶B（PKB）表达的部分降低相关。对细胞对各种损伤剂敏感性的研究表明，经地塞米松长期处理后的细胞具有对激素药物和缺氧的抗性水平升高的特征，同时对紫外线（UV）辐射或阿霉素等抗肿瘤药物高度敏感。结果显示，抗性细胞在缺氧条件下或短期接受地塞米松处理会导致PKB水平大幅升高，而UV辐射和阿霉素均不影响这些细胞中的PKB水平。我们证明，对黑色素瘤细胞进行长期地塞米松处理会导致有丝分裂原转导信号蛋白STAT3（信号转导子和转录激活子3）的活性形式积累，这也有助于诱导黑色素瘤细胞对地塞米松抗增殖作用产生抗性。我们认为，长期地塞米松处理后黑色素瘤细胞中PKB水平降低与PI3K/STAT3信号激活相结合，可能是这些细胞对激素药物和损伤剂具有不同敏感性的机制之一。本文还展示了体外培养肿瘤细胞激素抗性进展的模型。
