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A role for survivin in chemoresistance of endothelial cells mediated by VEGF

Jennifer M. TranMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8Zubin MasterMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8Joanne YuMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8Janusz RakMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8Daniel DumontMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8Robert S. KerbelMolecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada M5G 1L5; Department of Medical Biophysics, University of Toronto, ON, Canada M5G 2M9; and Deparment of Medicine, McMaster University, ON, Canada L8S 4L8

2002en

ABI

Annotatsiya

Although standard anticancer chemotherapeutic drugs have been designed to inhibit the survival or growth of rapidly dividing tumor cells, it is possible to enhance the efficacy of such drugs by targeting the proliferating host endothelial cells (ECs) of the tumor vasculature. A theoretical advantage of this strategy lies in the possibility of circumventing, or significantly delaying, acquired drug resistance driven by the genetic instability of tumor cells. Here, we show that both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor significantly reduce the pro-apoptotic potency of chemotherapy on both micro- and macrovascular ECs. This cytoprotection to drug toxicity was found to be phosphatidylinositol 3-kinase-dependent and could be recapitulated in the absence of VEGF by overexpressing the dominant-active form of the serine/threonine kinase protein kinase B/Akt. Downstream of phosphatidylinositol 3-kinase, we also show that survivin plays a pivotal role in VEGF-mediated EC protection by preserving the microtubule network. In this respect, its induction effectively protects ECs against chemotherapeutic damage, whereas overexpression of its dominant-interfering mutant (C84A) abrogates the protective effects of VEGF. Accordingly, the potency of VEGF as a chemoprotectant was more pronounced with drugs that interfere with microtubule dynamics than those that damage DNA. These studies implicate a role for survivin up-regulation as a novel mechanism of EC drug "resistance" and support the notion that angiogenic factors that induce the expression of survivin may act to shield tumor ECs from the apoptotic effects of chemotherapy. Thus, exploiting chemotherapeutic drugs as antiangiogenics is likely to be compromised by the high concentrations of proangiogenic survival/growth factors present in the tumor microenvironment; targeting EC survival pathways should improve the antiangiogenic efficacy of antineoplastic agents, particularly microtubule-inhibitor drugs.

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DOI: 10.1073/pnas.072586399

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