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 G2/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5–15-fold) within 4 h without G2/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 G2/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 G2/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. 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 G2/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5–15-fold) within 4 h without G2/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 G2/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 G2/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. Survivin is a recently characterized novel member of the inhibitor of apoptosis (IAP) 1The abbreviations used are: IAP, inhibitor of apoptosis; siRNA, small interfering RNA; PI3K, phosphatidylinositol 3-kinase; Erk or ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; BSA, bovine serum albumin; TBS-T, Tris-buffered saline plus Tween 20; DMEM, Dulbecco's modified Eagle's medium. protein family. It is undetectable in most normal adult tissues but highly expressed in cancer. Survivin expression has been shown to be associated with carcinogenesis, cancer progression, poor prognosis, drug resistance, and short patient survival (1Li F. J. Cell. 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Ther. 2002; 1: 113-117Crossref PubMed Scopus (40) Google Scholar). On the other hand, it has been demonstrated that survivin expression is cell cycle-regulated with a robust increase in the G2/M phase of cell cycle (2Li F. Ambrosini G. Chu E.Y. Plescia J. Tognin S. Marchisio P.C. Altieri D.C. Nature. 1998; 396: 580-584Crossref PubMed Scopus (1737) Google Scholar, 27Li F. Altieri D.C. Cancer Res. 1999; 59: 3143-3151PubMed Google Scholar). Presumably, cells treated with taxol should show an increased survivin expression because of G2/M arrest. Consistent with this notion, it was reported that taxol-induced microtubule stabilization and mitotic arrest increase survivin expression, which engenders a cell survival pathway to counteract taxol-induced apoptosis (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). However, it is not clear whether this mitotic survival pathway is the only means involving survivin by which cancer cells counteract taxol-induced apoptosis following drug treatment. Here, we that induction of survivin by taxol is an early event and is independent of taxol-mediated G2/M arrest. that taxol treatment of MCF-7 cancer cells rapidly up-regulated survivin expression without arrest of cells G2/M Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although the of cells in G2/M phase was significantly increased at later times. Consistent with the that 3 nm taxol survivin as effectively as 300 nm and more effectively than 3000 nm 3 nm taxol ineffective for apoptotic induction in these However, inhibition of taxol-mediated induction of survivin by small RNA significantly increased taxol-mediated cell death. that taxol rapidly activated the and Erk MAPK and inhibition of by or Erk MAPK by diminished survivin induction by taxol and sensitized cells to taxol-induced cell death. Survivin that early taxol-mediated induction of survivin is at least in and that the cis-acting DNA element the of taxol survivin is upstream of -1430 in the pLuc-2840 Together, these data show for the first that induction of survivin by taxol is an early event following drug and is independent of taxol-mediated G2/M arrest. This appears to be a new mechanism by which cancer cells evade taxol-induced apoptosis. Targeting this novel survival pathway may in cancer Cell a cancer cell without P-glycoprotein and expression, were in bovine serum and in a with at were and were from and were from and MAPK were from Cell and were from was from was from were 4 in and at to taxol treatment, the was with and 3000 and in to of and 3000 In the MCF-7 cells were treated with and 3000 nm taxol for In the MCF-7 cells were treated with nm taxol and at and h taxol treatment. In the MCF-7 cells were treated with 3 nm taxol. of the the was treated with the In for of pathways and cell MCF-7 cells were treated with and without taxol and in the and of of or and Survivin expression was by treatment for Cell were treatment for with and without treatment were with phosphate-buffered saline and and for in and the were by at for at 4 the protein was protein to of protein was in for at and to the the were with or bovine serum in and Tween for 3 h at with the were in the and at 4 with for the was in in the at for h with The or expression of the target protein was by the protein following the and by with the of protein the were with and and used for by the with a against and/or with the against the for of Cell to be were by and in A small of the cell was in at a because cells as A was the and one was with the cell a and cells were in of the and an cell was in this for times. The of cell in was with the of cell cell and taxol treatment as the cells were by and with were in of the cells were in of and A and for at least at 4 The cells were for by from from were were were the with in different 3 nm taxol treatment as was and cells were with and with in at 4 were and for in and survivin and DNA the cells were first in and for at by for at The DNA was with at a concentration of in for at The cells were with The cells were a were and with human survivin RNA with were and by as and of were to a concentration of in and at for the was at for and at for A RNA was as for a in this The and was not in cells by at In with were with survivin the following the to MCF-7 were in to a of at the of without The was by of of with of 3 of the in was with The was to the within in a of The cells were at for 4 and of bovine serum was were treated with and without 3 and nm taxol h with or as cells were h taxol treatment. of DNA cells were and h taxol treatment and by and as The of cells DNA was as a of the were at for cells were with survivin which a survivin F. Altieri D.C. Biochem. J. 1999; PubMed Scopus Google Scholar), the and were a to the were in to On the following the for well was by of and of DNA in a of medium. The DNA was at for and cells at in well medium. The cells were treated with 3 and/or nm taxol h for the and taxol and/or nm in was to the cells at other at 4 and h the first taxol treatment to the of the cells from of the were with and in of well h the taxol treatment. of the for the was to a by with a was by at for at 4 of cell was used to and a by of was to as and as a from a in of Survivin by Taxol an and of taxol-mediated G2/M was shown that taxol treatment of cells for h survivin expression to in taxol-mediated G2/M arrest (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). the taxol-mediated G2/M arrest and survivin induction, MCF-7 cells were treated with taxol at and times as shown and survivin expression was by taxol (48 h or significantly survivin induction in comparison with the early times The induction of survivin at h that induction of survivin expression at times. Consistent with this notion, to early taxol treatment that taxol-mediated survivin induction is as early as 4 h and that treatment times h diminished the of taxol survivin induction in comparison with This result that induction of survivin by taxol is independent of taxol-mediated G2/M arrest. this we cell cycle by and taxol treatment. As shown is G2/M cell increase at the 4 and times of taxol treatment in comparison with the taxol A increase of G2/M cell was only taxol treatment for h or more cells by survivin taxol treatment for 4 The results that cells increased with in comparison to taxol treatment A from the is shown in The G2/M induction of survivin expression by taxol was by the expression of G2/M phase taxol treatment. was in expression 4 h taxol treatment Interestingly, the protein was undetectable h taxol treatment that the cells were in later of taxol cell cycle and the expression of survivin and in MCF-7 were by and as cell cycle was by and taxol treatment at and shown as a the from a in Cell by in is shown in induction of survivin expression by taxol was by As survivin expression in cells was significantly increased 4 h taxol treatment in comparison with taxol treatment of induction of expression taxol treatment. The increase of protein to is of Taxol Survivin but for the induction of survivin expression by taxol at was as effective as or more effective than Consistent with the that expression of survivin cell and engenders drug resistance (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, N. M. G. P. R. S. F. Cell Mol. Sci. 2002; 59: PubMed Scopus Google Scholar, N.R. D.S. Plescia J. Y. Altieri D.C. Cancer Res. 2003; Google Scholar), of taxol were ineffective for induction of cell death in comparison with of the drug Inhibition of of Survivin by Cell a survivin Li F. Google Scholar) for inhibition of taxol-mediated survivin induction to the of survivin inhibition taxol-induced cell death. the of used in this Consistent with the result that survivin significantly the taxol-mediated induction of survivin in MCF-7 cells and that a of survivin and a concentration of taxol treatment increased cell death DNA in comparison with either treatment This that survivin expression a in cell and that induction of survivin by taxol is a drug resistance to cell Taxol and in MCF-7 has been shown that of the survival pathway can survivin expression A. D. K. D.S. Li F. Altieri D.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Z. J. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar) and inhibition of and can induction of survivin S. Porter S.B. L.M. 2002; PubMed Scopus Google Scholar). the mechanism by which taxol rapidly survivin expression, the of and taxol treatment was in MCF-7 Interestingly, the of and were rapidly and increased taxol treatment of these cells Inhibition of by or by Survivin and Cell whether inhibition of taxol-mediated by the diminished taxol-mediated survivin induction. of survivin was significantly decreased by the of taxol-mediated induction of survivin was in the of or whether inhibition of taxol-mediated and taxol-mediated we the of taxol treatment with either inhibitor or inhibitor cell death. The results that significantly increased the effectiveness of taxol to cell death of Survivin at in and a DNA of -1430 in pLuc-2840 for This whether taxol-mediated induction of survivin expression is the survivin construct a survivin F. Altieri D.C. Biochem. J. 1999; PubMed Scopus Google Scholar) was in MCF-7 cells were by and treated h with taxol for and h as were and were the and to Consistent with the results from and taxol increased the treatment the cis-acting DNA element responsible for the of taxol survivin a of survivin different of survivin F. Altieri D.C. Biochem. J. 1999; PubMed Scopus Google Scholar) were MCF-7 cells and treated with nm taxol for and h as h As a induction of was in the pLuc-2840 construct but not in or data that the cis-acting DNA element responsible for the of taxol induction of survivin is upstream of -1430 in the pLuc-2840 It was demonstrated that taxol-mediated mitotic arrest in cells was associated with of survivin expression to which engenders a survival pathway (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). This appears to be with the that the expression of survivin is cell with a robust increase at the G2/M phase of cell cycle (2Li F. Ambrosini G. Chu E.Y. Plescia J. Tognin S. Marchisio P.C. Altieri D.C. Nature. 1998; 396: 580-584Crossref PubMed Scopus (1737) Google Scholar, 27Li F. Altieri D.C. Cancer Res. 1999; 59: 3143-3151PubMed Google Scholar). However, in this study, we that taxol-mediated induction of survivin is a early event and is independent of taxol-induced mitotic arrest and that the of survivin by taxol survival that taxol-induced cell death. This was by induction of survivin by taxol as short as 4 h without of G2/M cell in This was by survivin to cells and by to the G2/M expression taxol treatment. survivin induction by taxol was significantly diminished a mitotic arrest following treatment (48 h or inhibition of taxol-mediated induction of survivin by significantly increased taxol-mediated cell death. with the in this that taxol treatment activated and MAPK of taxol-mediated and Erk by decreased taxol-mediated survivin induction and increased taxol-induced cell death. this is the first that taxol can a G2/M induction of which is for cell survival and resistance to taxol-induced cell death. This of the function of survivin to the of a cell survival pathway taxol treatment D.S. Grossman D. Plescia J. Li F. Zhang H. Villa A. Tognin S. Marchisio P.C. Altieri D.C. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13103-13107Crossref PubMed Scopus (588) Google Scholar, D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, N.R. D.S. Plescia J. Y. Altieri D.C. Cancer Res. 2003; Google Scholar) and new the mechanisms by which cancer cells cell survival pathways and taxol resistance. It was reported that taxol induces of the pathway of the cell death in human cancer cell J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), but the of the taxol treatment was not in that taxol treatment rapidly in MCF-7 cancer cells is with the we and demonstrated that of by and taxol-mediated survivin induction and taxol-induced cell death in MCF-7 provide an for that cells treated with taxol by a increase in and apoptosis C. S. P. S. Mol. Pharmacol. 60: PubMed Scopus Google Scholar). In this study, the of survivin in taxol-mediated cell survival was by survivin with Li F. Google the inhibition of taxol-induced survivin induction by increased taxol-induced cell death. In in this we that taxol treatment rapidly in to and inhibition of taxol-induced by inhibitor taxol-mediated survivin induction and cell death. This the of taxol-mediated cell survival and apoptosis. Interestingly, we that was significantly at h and increased at h taxol treatment although the of this is not clear and The most in is the that induction of survivin expression by taxol is an early event and is independent of taxol-mediated microtubule stabilization and mitotic arrest. this is with and by a of It was shown that taxol and apoptotic expression that is independent of microtubule stabilization Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar) and that of by inhibitor a cell apoptosis in human cells H. A. Cancer Res. Google Scholar). In this one to that inhibition of taxol-mediated survivin induction increased cell death be that of survivin the of of and of apoptosis. of the mechanism by which induction of survivin by taxol to preserves a cell survival pathway may for cancer and in A demonstrated that in MCF-7 cancer although and were by of and to the of that the A.L. P.A. S. K. J. M. S.H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). for the of and is that the rapidly taxol-induced survivin expression in this may with to However, evidence for survivin to activated is In inhibition of as and by survivin is (1Li F. J. Cell. Physiol. 2003; 197: 8-29Crossref PubMed Scopus (307) Google Scholar). that survivin not Huang H. E. T. Nat. Biol. 2000; PubMed Scopus Google Scholar, Plescia J. Altieri D.C. J. Rosenberg S.H. Zhang H. Ng S.C. 2000; PubMed Google Scholar), that it Y. E. N. T. Reed J.C. Cancer Res. 1998; Google Scholar, S. Y.K. PubMed Scopus Google Scholar). Interestingly, a that survivin with by taxol treatment Z. Wu M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in a that survivin and only in the of that the of survivin with from to This is a to in this that inhibition of taxol-mediated induction of survivin by or by increased apoptosis by taxol. However, to it is to that survivin has to than in the and/or of taxol treatment. The we to is the mechanism that is in taxol-mediated induction of survivin of a of survivin different of survivin F. Altieri D.C. Biochem. J. 1999; PubMed Scopus Google Scholar) MCF-7 cells by taxol treatment that a cis-acting DNA element upstream of -1430 in the pLuc-2840 construct is responsible for the of taxol of survivin Consistent with this show that of cells with the survivin construct (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar) or of MCF-7 cells with the survivin construct of survivin N.R. D.S. Plescia J. Y. Altieri D.C. Cancer Res. 2003; Google Scholar) to the induction of survivin by taxol. we that taxol survivin the construct or the However, the increase by taxol not for the of induction of survivin protein by taxol in in this This that a mechanism may be in taxol-mediated survivin induction. show that the of survivin at by kinase survivin protein (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). However, this mechanism is for the results reported because survivin protein was increased taxol treatment as short as 4 h without a increase of the and the G2/M cell and taxol-mediated induction of survivin protein decreased a taxol-mediated G2/M arrest for h in comparison with the early following taxol treatment. It was shown that kinase has its at this (28O'Connor D.S. Wall N.R. Porter A.C. Altieri D.C. Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). of mechanisms is in In although it is that taxol treatment induces cells to arrest at (18Kumar N. J. Biol. Chem. 1981; 256: 10435-10441Abstract Full Text PDF PubMed Google Scholar), we that taxol-mediated induction of survivin in the cell cycle and is independent of taxol-mediated mitotic arrest. The induction of survivin by taxol to increase cell and resistance to apoptosis by taxol. Targeting this survival pathway may result in novel approaches for cancer therapeutics.

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