2-Methoxyestradiol (2ME2) is a naturally occurring derivative of estradiol currently in Phase l/ll clinical trials as an inhibitor of tumor angiogenesis. We have recently reported that 2ME2 potently inhibits the protein levels and transcriptional activity of the pro-angiogenic and pro-survival transcription factor HIF-1 alpha. Moreover, we showed that HIF-1 alpha inhibition occurs downstream of disruption of the microtubule cytoskeleton by 2ME2. These data provide the first mechanistic link between targeting of the microtubule cytoskeleton and inhibition of tumor angiogenesis. However, the cellular signals that lead from microtubule disruption to HIF-1 alpha inhibition remain unknown. With this proposal, we seek to build upon our previous work in order to investigate in detail the molecular mechanism(s) that lead from microtubule disruption to inhibition of tumor angiogenesis and survival. Our hypothesis is that 2ME2 has a bivalent effect on the chemomechanics of microtubule-dependent HIF-1 alpha activation. By disrupting cellular microtubules, 2ME2 inhibits HIF-1 alpha nuclear translocation and HIF-1 alpha translation, thus, resulting in inhibition of HIF-1 alpha activity. To elucidate the mechanism by which microtubule disruption regulates HIF-1 alpha activity we plan to: I) Elucidate the mechanism by which 2ME2 inhibits HIF-1 nuclear translocation, II) Define the mechanism by which 2ME2 inhibits HIF-1 alpha translation and III) Investigate whether abrogation of microtubule-dependent regulation of HIF-1 alpha in VHL-mutant renal cell carcinomas (RCCs), results in 2ME2 resistance. We will also expand these observations to additional classes of microtubule-targeting drugs, such as the taxanes, the epothilones and the vinca alkaloids. With this proposal we are seeking to build on our previous work and advance our understanding of the basic mechanisms governing the microtubule-dependent regulation of the HIF pathway, as well as their impact on tumor survival and chemosensitivity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114335-04
Application #
7233248
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Ault, Grace S
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$283,146
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Carbonaro, Marisa; Escuin, Daniel; O'Brate, Aurora et al. (2012) Microtubules regulate hypoxia-inducible factor-1? protein trafficking and activity: implications for taxane therapy. J Biol Chem 287:11859-69
Kong, Koon Yin; Marcus, Adam I; Giannakakou, Paraskevi et al. (2012) Integrating image analysis algorithms in a web interface for the quantification of microtubule dynamics. Int J Comput Biol Drug Des 5:298-313
Kong, Koon Yin; Marcus, Adam I; Giaanakakou, Paraskevi et al. (2011) A Web Interface for the Quantification of Microtubule Dynamics. IEEE Int Conf Bioinform Biomed Workshops 2011:209-214
Kanakkanthara, Arun; Wilmes, Anja; O'Brate, Aurora et al. (2011) Peloruside- and laulimalide-resistant human ovarian carcinoma cells have ?I-tubulin mutations and altered expression of ?II- and ?III-tubulin isotypes. Mol Cancer Ther 10:1419-29
Carbonaro, Marisa; O'Brate, Aurora; Giannakakou, Paraskevi (2011) Microtubule disruption targets HIF-1alpha mRNA to cytoplasmic P-bodies for translational repression. J Cell Biol 192:83-99
Zhou, Jun; Vos, Chantal Chanel; Gjyrezi, Ada et al. (2009) The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. J Biol Chem 284:9648-55
Escuin, Daniel; Burke, Patricia A; McMahon-Tobin, Grainne et al. (2009) The hematopoietic-specific beta1-tubulin is naturally resistant to 2-methoxyestradiol and protects patients from drug-induced myelosuppression. Cell Cycle 8:3914-24
Thomas, Shala L; Zhong, Diansheng; Zhou, Wei et al. (2008) EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle 7:2409-17
Mun, Jiyoung; Wang, Yuefang; Voll, Ronald J et al. (2008) Syntheses and biological activities of novel 2-methoxyestradiol analogs, 2-fluoroethoxyestradiol and 2-fluoropropanoxyestradiol, and a radiosynthesis of 2-[(18)F]fluoroethoxyestradiol for positron emission tomography. Nucl Med Biol 35:615-22
Marcus, Adam I; O'Brate, Aurora M; Buey, Ruben M et al. (2006) Farnesyltransferase inhibitors reverse taxane resistance. Cancer Res 66:8838-46

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