Taxane-mediated gene induction is independent of microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis.
Pharmacological traits of the antineoplastic agent taxol may originate in part from its effects on gene expression and not simply from its effects on microtubule assembly. This prompts three questions. First, how extensive is gene induction by taxol? Second, is gene induction confined to taxol itself, or does it occur with other taxane analogs? Third, do the functions of any induced genes correspond with known attributes of taxol or taxane analogs? We report that taxol induces numerous early-response genes, not just cytokine genes. Previously unidentified taxol-induced genes include genes coding transcription factors with tumor suppressor effects (krox-24) and enzymes that govern proliferation, apoptosis, and inflammation (2'5'-oligoadenylate synthase, cyclooxygenase-2, and an IkappaB kinase termed chuk). Taxotere, a potent analog of taxol, did not induce any of these genes, implying that taxol modulates gene expression by a mechanism that is distinct from microtubule stabilization and cell cycle arrest. Other taxane analogs induce some of the same genes as taxol, indicating that this process is not unique to taxol. Functional changes coincided with changes in gene expression. For instance, induction of tumor necrosis factor alpha (TNFalpha) accentuated apoptosis in cells treated with taxol compared with corresponding cells treated with taxotere. The functions of several induced genes (e.g., krox-24 and cyclooxygenase-2) are self-consistent with beneficial and adverse effects encountered during taxol administration. These results may be relevant to the safe and effective use of taxol or its analogs in oncology and other areas of medicine.
Moos
P J
PJ
Huntsman Cancer Institute, University of Utah, 546 Chipeta Way #1100, Salt Lake City, UT 84108, USA.
Fitzpatrick
F A
FA
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects*; D051550:I-kappa B Kinase; D017874:Immediate-Early Proteins; D007249:Inflammation / Q000235:genetics*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000502:physiology* / Q000648:ultrastructure*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D043823:Taxoids; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation
D001952:Bridged-Ring Compounds; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D043823:Taxoids; D014157:Transcription Factors; C080625:taxane; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse