Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1

Michael H. Muders, Heyu Zhang, Enfeng Wang, Donald J. Tindall, Kaustubh Datta

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C(VEGF-C ) in metastatic prostate cancer. We have discovered that VEGF-Cacts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/protein kinase BA. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-Cin protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-Cin inducing lymphangiogenesis.

Original languageEnglish (US)
Pages (from-to)6042-6048
Number of pages7
JournalCancer Research
Volume69
Issue number15
DOIs
StatePublished - Aug 1 2009

Fingerprint

Vascular Endothelial Growth Factor C
Prostatic Neoplasms
Oxidative Stress
Vascular Endothelial Growth Factor A
Neoplasms
Neuropilin-2
Lymphangiogenesis
Recurrence
Microarray Analysis
TOR complex 2
Protein Kinases
Hydrogen Peroxide
Intercellular Signaling Peptides and Proteins
Cell Death
Phosphotransferases
Neoplasm Metastasis
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1. / Muders, Michael H.; Zhang, Heyu; Wang, Enfeng; Tindall, Donald J.; Datta, Kaustubh.

In: Cancer Research, Vol. 69, No. 15, 01.08.2009, p. 6042-6048.

Research output: Contribution to journalArticle

@article{b9052d71a69144d79c277635b5d0b3cf,
title = "Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1",
abstract = "Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C(VEGF-C ) in metastatic prostate cancer. We have discovered that VEGF-Cacts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/protein kinase BA. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-Cin protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-Cin inducing lymphangiogenesis.",
author = "Muders, {Michael H.} and Heyu Zhang and Enfeng Wang and Tindall, {Donald J.} and Kaustubh Datta",
year = "2009",
month = "8",
day = "1",
doi = "10.1158/0008-5472.CAN-09-0552",
language = "English (US)",
volume = "69",
pages = "6042--6048",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "15",

}

TY - JOUR

T1 - Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1

AU - Muders, Michael H.

AU - Zhang, Heyu

AU - Wang, Enfeng

AU - Tindall, Donald J.

AU - Datta, Kaustubh

PY - 2009/8/1

Y1 - 2009/8/1

N2 - Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C(VEGF-C ) in metastatic prostate cancer. We have discovered that VEGF-Cacts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/protein kinase BA. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-Cin protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-Cin inducing lymphangiogenesis.

AB - Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C(VEGF-C ) in metastatic prostate cancer. We have discovered that VEGF-Cacts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/protein kinase BA. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-Cin protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-Cin inducing lymphangiogenesis.

UR - http://www.scopus.com/inward/record.url?scp=68049131465&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68049131465&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-0552

DO - 10.1158/0008-5472.CAN-09-0552

M3 - Article

C2 - 19638584

AN - SCOPUS:68049131465

VL - 69

SP - 6042

EP - 6048

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 15

ER -