Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest.
Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G(2)/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5-15-fold) within 4 h without G(2)/M arrest. Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although G(2)/M cells were significantly increased at later times. Interestingly, 3 nm taxol induces survivin as effectively as 300 nm and more effectively than 3000 nm. As a result, 3 nm taxol is ineffective at inducing cell death. However, inhibition of taxol-mediated survivin induction by small interfering RNA significantly increased taxol-mediated cell death. Taxol rapidly activated the phosphatidylinositol 3-kinase/Akt and MAPK pathways. Inhibition of these pathways diminished survivin induction and sensitized cells to taxol-mediated cell death. A cis-acting DNA element upstream of -1430 in the survivin pLuc-2840 construct is at least partially responsible for taxol-mediated survivin induction. Together, these data show, for the first time, that taxol-mediated induction of survivin is an early event and independent of taxol-mediated G(2)/M arrest. This appears to be a new mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this survival pathway may result in novel approaches for cancer therapeutics.
Ling
Xiang
X
Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. fengzhi.li@roswellpark.org
Bernacki
Ralph J
RJ
Brattain
Michael G
MG
Li
Fengzhi
F
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D008938:Mitosis; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011419:Propidium / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D014343:Trypan Blue / Q000494:pharmacology; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; D004396:Coloring Agents; D019926:Cyclin B; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D011419:Propidium; D004247:DNA; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; D014343:Trypan Blue; D017239:Paclitaxel