Role of Phosphatidylinositol-3 Kinase in Regulation of Differential Sensitivity of Melanoma Cells to Antitumor Agents. A Model for Hormone Resistance Development in Tumor Cells

M. A. Krasil'nikov^1*, E. V. Luzai¹, A. M. Scherbakov², V. A. Shatskaya¹, A. A. Shtil¹, and E. S. Gershtein²

¹Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, Moscow 115478, Russia; fax: (7-095) 324-1205; E-mail: krasilnikovm@mail.ru

²Institute of Clinical Oncology, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia; fax: (7-095) 324-6352

^* To whom correspondence should be addressed.

Received June 17, 2003; Revision received September 12, 2003

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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.

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KEY WORDS: melanoma, phosphatidylinositol-3 kinase, protein kinase B, STAT3, dexamethasone, resistance, apoptosis

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