This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wall, N. R. Articles by Altieri, D. C. Search for Related Content PubMed PubMed Citation Articles by Wall, N. R. Articles by Altieri, D. C.

Suppression of Survivin Phosphorylation on Thr³⁴ by Flavopiridol Enhances Tumor Cell Apoptosis¹

Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605 [N. R. W., D. S. O., J. P., D. C. A.], and Laboratory of Molecular Pharmacology, National Cancer Institute/NIH, Bethesda, Maryland 20892 [Y. P.]

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4–5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr³⁴ by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr³⁴Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr³⁴ enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr³⁴ phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34^cdc2 kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.

This article has been cited by other articles:

				N. Bhatnagar, X. Li, Y. Chen, X. Zhou, S. H. Garrett, and B. Guo 3,3'-Diindolylmethane Enhances the Efficacy of Butyrate in Colon Cancer Prevention through Down-Regulation of Survivin Cancer Prevention Research, June 1, 2009; 2(6): 581 - 589. [Abstract] [Full Text] [PDF]

				K. W. Rahman, S. Banerjee, S. Ali, A. Ahmad, Z. Wang, D. Kong, and W. A. Sakr 3,3'-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation Cancer Res., May 15, 2009; 69(10): 4468 - 4475. [Abstract] [Full Text] [PDF]

				J. Wang, Y. Jin, Z. Xu, Z. Zheng, and S. Wan Involvement of Caspase-3 Activity and Survivin Downregulation in Cinobufocini-Induced Apoptosis in A 549 Cells Experimental Biology and Medicine, May 1, 2009; 234(5): 566 - 572. [Abstract] [Full Text] [PDF]

				A Scholz, K Wagner, M Welzel, F Remlinger, B Wiedenmann, G Siemeister, S Rosewicz, and K M Detjen The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model Gut, February 1, 2009; 58(2): 261 - 270. [Abstract] [Full Text] [PDF]

				Z. Yue, A. Carvalho, Z. Xu, X. Yuan, S. Cardinale, S. Ribeiro, F. Lai, H. Ogawa, E. Gudmundsdottir, R. Gassmann, et al. Deconstructing Survivin: comprehensive genetic analysis of Survivin function by conditional knockout in a vertebrate cell line J. Cell Biol., October 20, 2008; 183(2): 279 - 296. [Abstract] [Full Text] [PDF]

				T. Iwasa, I. Okamoto, M. Suzuki, T. Nakahara, K. Yamanaka, E. Hatashita, Y. Yamada, M. Fukuoka, K. Ono, and K. Nakagawa Radiosensitizing Effect of YM155, a Novel Small-Molecule Survivin Suppressant, in Non-Small Cell Lung Cancer Cell Lines Clin. Cancer Res., October 15, 2008; 14(20): 6496 - 6504. [Abstract] [Full Text] [PDF]

				C. Zhang, K. Lundgren, Z. Yan, M. E. Arango, S. Price, A. Huber, J. Higgins, G. Troche, J. Skaptason, T. Koudriakova, et al. Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy Mol. Cancer Ther., April 1, 2008; 7(4): 818 - 828. [Abstract] [Full Text] [PDF]

				H. Hu, G.-x. Li, L. Wang, J. Watts, G. F. Combs Jr., and J. Lu Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates Antiapoptotic Proteins Bcl-XL and Survivin Clin. Cancer Res., February 15, 2008; 14(4): 1150 - 1158. [Abstract] [Full Text] [PDF]

				O. Rixe and T. Fojo Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient? Clin. Cancer Res., December 15, 2007; 13(24): 7280 - 7287. [Abstract] [Full Text] [PDF]

				J.-I Chao, W.-C. Su, and H.-F. Liu Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT Mol. Cancer Ther., November 1, 2007; 6(11): 3039 - 3048. [Abstract] [Full Text] [PDF]

				T. Nakahara, M. Takeuchi, I. Kinoyama, T. Minematsu, K. Shirasuna, A. Matsuhisa, A. Kita, F. Tominaga, K. Yamanaka, M. Kudoh, et al. YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts Cancer Res., September 1, 2007; 67(17): 8014 - 8021. [Abstract] [Full Text] [PDF]

				J. Y. Chun, Y. Hu, E. Pinder, J. Wu, F. Li, and A. C. Gao Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter Mol. Cancer Ther., September 1, 2007; 6(9): 2572 - 2580. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, L. Douglas, J. L. Cleveland, R. Humphreys, and J. A. Houghton Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels Cancer Res., July 15, 2007; 67(14): 6987 - 6994. [Abstract] [Full Text] [PDF]

				A. Ferrario, N. Rucker, S. Wong, M. Luna, and C. J. Gomer Survivin, a Member of the Inhibitor of Apoptosis Family, Is Induced by Photodynamic Therapy and Is a Target for Improving Treatment Response Cancer Res., May 15, 2007; 67(10): 4989 - 4995. [Abstract] [Full Text] [PDF]

				X. Huang and B. Guo Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. Cancer Res., September 15, 2006; 66(18): 9245 - 9251. [Abstract] [Full Text] [PDF]

				C. Palacios, R. Yerbes, and A. Lopez-Rivas Flavopiridol Induces Cellular FLICE-Inhibitory Protein Degradation by the Proteasome and Promotes TRAIL-Induced Early Signaling and Apoptosis in Breast Tumor Cells. Cancer Res., September 1, 2006; 66(17): 8858 - 8869. [Abstract] [Full Text] [PDF]

				B. H. Kang and D. C. Altieri Regulation of Survivin Stability by the Aryl Hydrocarbon Receptor-interacting Protein J. Biol. Chem., August 25, 2006; 281(34): 24721 - 24727. [Abstract] [Full Text] [PDF]

				B. Z. Carter, D. H. Mak, W. D. Schober, T. McQueen, D. Harris, Z. Estrov, R. L. Evans, and M. Andreeff Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells Blood, July 15, 2006; 108(2): 630 - 637. [Abstract] [Full Text] [PDF]

				F. Li and M. G. Brattain Role of the SurvivinGene in Pathophysiology Am. J. Pathol., July 1, 2006; 169(1): 1 - 11. [Abstract] [Full Text] [PDF]

				E. B. Sambol, G. Ambrosini, R. C. Geha, P. T. Kennealey, P. DeCarolis, R. O'Connor, Y. V. Wu, M. Motwani, J.-H. Chen, G. K. Schwartz, et al. Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells Cancer Res., June 1, 2006; 66(11): 5858 - 5866. [Abstract] [Full Text] [PDF]

				S. Fukuda and L. M. Pelus Survivin, a cancer target with an emerging role in normal adult tissues Mol. Cancer Ther., May 1, 2006; 5(5): 1087 - 1098. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF]

				B. M. Ryan, G. E. Konecny, S. Kahlert, H.-J. Wang, M. Untch, G. Meng, M. D. Pegram, K. C. Podratz, J. Crown, D. J. Slamon, et al. Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1 Ann. Onc., April 1, 2006; 17(4): 597 - 604. [Abstract] [Full Text] [PDF]

				D. C. Altieri Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. Mol. Cancer Ther., March 1, 2006; 5(3): 478 - 482. [Abstract] [Full Text] [PDF]

				W. Xia, J. Bisi, J. Strum, L. Liu, K. Carrick, K. M. Graham, A. L. Treece, M. A. Hardwicke, M. Dush, Q. Liao, et al. Regulation of Survivin by ErbB2 Signaling: Therapeutic Implications for ErbB2-Overexpressing Breast Cancers Cancer Res., February 1, 2006; 66(3): 1640 - 1647. [Abstract] [Full Text] [PDF]

				J.-I Chao and H.-F. Liu The Blockage of Survivin and Securin Expression Increases the Cytochalasin B-Induced Cell Death and Growth Inhibition in Human Cancer Cells Mol. Pharmacol., January 1, 2006; 69(1): 154 - 164. [Abstract] [Full Text] [PDF]

				G. K. Schwartz and M. A. Shah Targeting the Cell Cycle: A New Approach to Cancer Therapy J. Clin. Oncol., December 20, 2005; 23(36): 9408 - 9421. [Abstract] [Full Text] [PDF]

				S. A.J. Vaziri, J. Hill, K. Chikamori, D. R. Grabowski, N. Takigawa, M. Chawla-Sarkar, L. R. Rybicki, A. V. Gudkov, T. Mekhail, R. M. Bukowski, et al. Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3{sigma} and survivin Mol. Cancer Ther., December 1, 2005; 4(12): 1880 - 1890. [Abstract] [Full Text] [PDF]

				R. L. Bevins and S. G. Zimmer It's About Time: Scheduling Alters Effect of Histone Deacetylase Inhibitors on Camptothecin-Treated Cells Cancer Res., August 1, 2005; 65(15): 6957 - 6966. [Abstract] [Full Text] [PDF]

				G. K. Schwartz Development of Cell Cycle Active Drugs for the Treatment of Gastrointestinal Cancers: A New Approach to Cancer Therapy J. Clin. Oncol., July 10, 2005; 23(20): 4499 - 4508. [Abstract] [Full Text] [PDF]

				K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF]

				M. A. Shah, J. Kortmansky, M. Motwani, M. Drobnjak, M. Gonen, S. Yi, A. Weyerbacher, C. Cordon-Cardo, R. Lefkowitz, B. Brenner, et al. A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol Clin. Cancer Res., May 15, 2005; 11(10): 3836 - 3845. [Abstract] [Full Text] [PDF]

				H. Li, J. Y. Niederkorn, S. Neelam, and H. Alizadeh Resistance and Susceptibility of Human Uveal Melanoma Cells to TRAIL-Induced Apoptosis Arch Ophthalmol, May 1, 2005; 123(5): 654 - 661. [Abstract] [Full Text] [PDF]

				J. Wu, X. Ling, D. Pan, P. Apontes, L. Song, P. Liang, D. C. Altieri, T. Beerman, and F. Li Molecular Mechanism of Inhibition of Survivin Transcription by the GC-rich Sequence-selective DNA Binding Antitumor Agent, Hedamycin: EVIDENCE OF SURVIVIN DOWN-REGULATION ASSOCIATED WITH DRUG SENSITIVITY J. Biol. Chem., March 11, 2005; 280(10): 9745 - 9751. [Abstract] [Full Text] [PDF]

				Y.-T. Huang, D.-M. Huang, J.-H. Guh, I-L. Chen, C.-C. Tzeng, and C.-M. Teng CIL-102 Interacts with Microtubule Polymerization and Causes Mitotic Arrest following Apoptosis in the Human Prostate Cancer PC-3 Cell Line J. Biol. Chem., January 28, 2005; 280(4): 2771 - 2779. [Abstract] [Full Text] [PDF]

				P.-C. Kuo, H.-F. Liu, and J.-I Chao Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells J. Biol. Chem., December 31, 2004; 279(53): 55875 - 55885. [Abstract] [Full Text] [PDF]

				N. Gao, Y. Dai, M. Rahmani, P. Dent, and S. Grant Contribution of Disruption of the Nuclear Factor-{kappa}B Pathway to Induction of Apoptosis in Human Leukemia Cells by Histone Deacetylase Inhibitors and Flavopiridol Mol. Pharmacol., October 1, 2004; 66(4): 956 - 963. [Abstract] [Full Text] [PDF]

				R. I. Haddad, L. J. Weinstein, T. J. Wieczorek, N. Bhattacharya, H. Raftopoulos, M. W. Oster, X. Zhang, V. M. Latham Jr., R. Costello, J. Faucher, et al. A Phase II Clinical and Pharmacodynamic Study of E7070 in Patients with Metastatic, Recurrent, or Refractory Squamous Cell Carcinoma of the Head and Neck: Modulation of Retinoblastoma Protein Phosphorylation by a Novel Chloroindolyl Sulfonamide Cell Cycle Inhibitor Clin. Cancer Res., July 15, 2004; 10(14): 4680 - 4687. [Abstract] [Full Text] [PDF]

				S. Grant and P. Dent Gene profiling and the cyclin-dependent kinase inhibitor flavopiridol: What's in a name? Mol. Cancer Ther., July 1, 2004; 3(7): 873 - 875. [Full Text] [PDF]

				M. Pennati, M. Binda, M. De Cesare, G. Pratesi, M. Folini, L. Citti, M. G. Daidone, F. Zunino, and N. Zaffaroni Ribozyme-mediated down-regulation of survivin expression sensitizes human melanoma cells to topotecan in vitro and in vivo Carcinogenesis, July 1, 2004; 25(7): 1129 - 1136. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol Clin. Cancer Res., June 15, 2004; 10(12): 4270S - 4275S. [Abstract] [Full Text] [PDF]

				J.-I Chao, P.-C. Kuo, and T.-S. Hsu Down-regulation of Survivin in Nitric Oxide-induced Cell Growth Inhibition and Apoptosis of the Human Lung Carcinoma Cells J. Biol. Chem., May 7, 2004; 279(19): 20267 - 20276. [Abstract] [Full Text] [PDF]

				E. J. Schlette, L. J. Medeiros, A. Goy, R. Lai, and G. Z. Rassidakis Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma J. Clin. Oncol., May 1, 2004; 22(9): 1682 - 1688. [Abstract] [Full Text] [PDF]

				B. Lu, Y. Mu, C. Cao, F. Zeng, S. Schneider, J. Tan, J. Price, J. Chen, M. Freeman, and D. E. Hallahan Survivin As a Therapeutic Target for Radiation Sensitization in Lung Cancer Cancer Res., April 15, 2004; 64(8): 2840 - 2845. [Abstract] [Full Text] [PDF]

				X. Ling, R. J. Bernacki, M. G. Brattain, and F. Li Induction of Survivin Expression by Taxol (Paclitaxel) Is an Early Event, Which Is Independent of Taxol-mediated G2/M Arrest J. Biol. Chem., April 9, 2004; 279(15): 15196 - 15203. [Abstract] [Full Text] [PDF]

				D. M. Nguyen, W. D. Schrump, G. A. Chen, W. Tsai, P. Nguyen, J. B. Trepel, and D. S. Schrump Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells Clin. Cancer Res., March 1, 2004; 10(5): 1813 - 1825. [Abstract] [Full Text] [PDF]

				S. Fulda and K.-M. Debatin Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol Cancer Res., January 1, 2004; 64(1): 337 - 346. [Abstract] [Full Text] [PDF]

				S. P. Tu, X. H. Jiang, M. C. M. Lin, J. T. Cui, Y. Yang, C. T. Lum, B. Zou, Y. B. Zhu, S. H. Jiang, W. M. Wong, et al. Suppression of Survivin Expression Inhibits in Vivo Tumorigenicity and Angiogenesis in Gastric Cancer Cancer Res., November 15, 2003; 63(22): 7724 - 7732. [Abstract] [Full Text] [PDF]

				L. Yang, Z. Cao, H. Yan, and W. C. Wood Coexistence of High Levels of Apoptotic Signaling and Inhibitor of Apoptosis Proteins in Human Tumor Cells: Implication for Cancer Specific Therapy Cancer Res., October 15, 2003; 63(20): 6815 - 6824. [Abstract] [Full Text] [PDF]

				L. Zhang, S. Sharma, L. X. Zhu, T. Kogai, J. M. Hershman, G. A. Brent, S. M. Dubinett, and M. Huang Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells Cancer Res., August 15, 2003; 63(16): 5065 - 5072. [Abstract] [Full Text] [PDF]