[The molecular mechanism responsible for the adaptation of malignant tumors to hormonal drugs: a role of phophatidylinositol-3-kinase and phosphoinositide-dependent proteins].
Phophatidylinositol-3-kinase (PI3K) is a major intracellular protein that is responsible for the transmission of an antiapoptotic signal and controls the survival of tumor cells upon exposure to damaging agents. Experiments using different tumor cell cultures have shown that the resistance of cells to the antiproliferative action of dexamethasone, caused by their long cultivation with the hormone, is associated with the activation of PI3K and the transcription factor STATS. The activation of PI3K and STAT3 in the dexamethasone-resistant cells correlates with the increase in the total thyrosine kinase activity and with the decrease in the sensitivity of cells to exogenous proliferative agents, such as 17beta-estradiol. The long exposure of hormone-sensitive cells to nonhormonal factors that activate the PI3K/STAT3 signaling pathway, hypoxia in particular, has been shown to suffice to reduce the degree of hormonal tumor cell dependence. VEGF-A, an angiogenic peptide whose action was partially realizes through the PI3K-signalling pathway, has been demonstrated to be involved in the maintenance of cell growth, including the growth of hormone-independent cells. The findings suggest that complex changes in the antiapoptotic and mitogenic signaling pathways associated with PI3K, which ensures the autonomic, hormone-independent growth of tumor cells, may underlie the decreased hormonal dependence of tumor cells. Whether PI3K may be used to suppress the growth of hormone-independent tumors is discussed.
Pavlichenko
O V
OV
Shatskaia
V A
VA
Luzaĭ
E V
EV
Shcherbakov
A M
AM
Gershteĭn
E S
ES
Krasil'nikov
M A
MA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000627:therapeutic use; D010716:Phosphatidylinositols / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D010716:Phosphatidylinositols; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases