TY - JOUR
T1 - 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF
AU - Mabjeesh, Nicola J.
AU - Escuin, Daniel
AU - LaVallee, Theresa M.
AU - Pribluda, Victor S.
AU - Swartz, Glenn M.
AU - Johnson, Michelle S.
AU - Willard, Margaret T.
AU - Zhong, Hua
AU - Simons, Jonathan W.
AU - Giannakakou, Paraskevi
N1 - Funding Information:
This work was supported in part by the Avon Foundation with funds raised through the Avon Breast Cancer Crusade, NIH Prostate Cancer SPORE Grant CA-58236, CaP CURE Foundation, and Parisian (N.J.M., H.Z., J.W.S.). N.J.M. is recipient of a fellowship from The American Physicians Fellowship for Medicine in Israel. We wish to thank Dr. Paula Vertino and the Honorable Hamilton Jordan (Winship Cancer Institute, Emory University) for critical discussions and reading of the manuscript and Dr. Dimitris Papanicolaou (Endocrine Division, Emory University School of Medicine) for providing the Glut-1 probe. Finally, we would like to thank Carrie Fredrickson, Cristina Bush, Adam Marcus, Yuefang Wang, and Paula Checchi for technical assistance.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-α downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
AB - Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-α downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
UR - http://www.scopus.com/inward/record.url?scp=10744231706&partnerID=8YFLogxK
U2 - 10.1016/S1535-6108(03)00077-1
DO - 10.1016/S1535-6108(03)00077-1
M3 - Article
AN - SCOPUS:10744231706
SN - 1535-6108
VL - 3
SP - 363
EP - 375
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
