A role for survivin in chemoresistance of endothelial cells mediated by VEGF.
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.
Tran
Jennifer
J
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5.
Master
Zubin
Z
Yu
Joanne L
JL
Rak
Janusz
J
Dumont
Daniel J
DJ
Kerbel
Robert S
RS
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D019610:Cytoprotection; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000737:chemistry; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002868:Chromosomal Proteins, Non-Histone; D016228:Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C107489:BIRC5 protein, human; C494918:AKT1 protein, human