Oxygen-mediated regulation of tumor cell invasiveness - Involvement of a nitric oxide signaling pathway

被引:86
作者
Postovit, LM
Adams, MA
Lash, GE
Heaton, JP
Graham, CH
机构
[1] Queens Univ, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada
[2] Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada
[3] Queens Univ, Dept Urol, Kingston, ON K7L 3N6, Canada
关键词
D O I
10.1074/jbc.M204529200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor hypoxia is associated with a poor prognosis for patients with various cancers, often resulting in an increase in metastasis. Moreover, exposure to hypoxia increases the ability of breast carcinoma cells to invade the extracellular matrix, an important aspect of metastasis. Here, we demonstrate that the hypoxic upregulation of invasiveness is linked to reduced nitric oxide signaling. Incubation of human breast carcinoma cells in 0.5% versus 20% oxygen increased their in vitro invasiveness and their expression of the urokinase receptor, an invasion-associated molecule. These effects of hypoxia were inhibited by nitric oxidemimetic drugs; and in a manner similar to hypoxia, pharmacological inhibition of nitric oxide synthesis increased urokinase receptor expression. The nitric oxide signaling pathway involves activation of soluble guanylyl cyclase (sGC) and the subsequent activation of protein kinase G (PKG). Culture of tumor cells under hypoxic conditions (0.5% versus 20% oxygen) resulted in lower cGMP levels, an effect that could be prevented by incubation with glyceryl trinitrate. Inhibition of sGC activity with a selective blocker or with the heme biosynthesis inhibitor desferrioxamine increased urokinase receptor expression. These compounds also prevented the glyceryl trinitrate-mediated suppression of urokinase receptor expression in cells incubated under hypoxic conditions. In contrast, direct activation of PKG using 8-bromo-cGMP prevented the hypoxia- and desferrioxamine-induced increases in urokinase receptor expression as well as the hypoxia-mediated enhanced invasiveness. Further involvement of PKG in the regulation of invasion-associated phenotypes was established using a selective PKG inhibitor, which alone increased urokinase receptor expression. These findings reveal that an important mechanism by which hypoxia increases tumor cell invasiveness (and possibly metastasis) requires inhibition of the nitric oxide signaling pathway involving sGC and PKG activation.
引用
收藏
页码:35730 / 35737
页数:8
相关论文
共 40 条
[1]  
Brown JM, 1999, CANCER RES, V59, P5863
[2]   BREAST TUMOR-CELL LINES FROM PLEURAL EFFUSIONS [J].
CAILLEAU, R ;
YOUNG, R ;
OLIVE, M ;
REEVES, WJ .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1974, 53 (03) :661-674
[3]  
Cairns RA, 2001, CANCER RES, V61, P8903
[4]   PREVENTION OF METASTASIS BY INHIBITION OF THE UROKINASE RECEPTOR [J].
CROWLEY, CW ;
COHEN, RL ;
LUCAS, BK ;
LIU, GH ;
SHUMAN, MA ;
LEVINSON, AD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (11) :5021-5025
[5]  
Cuvier C, 1997, CLIN EXP METASTAS, V15, P19
[6]   Guanylate cyclase and the .NO/cGMP signaling pathway [J].
Denninger, JW ;
Marletta, MA .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1999, 1411 (2-3) :334-350
[7]   Nitric oxide synthesis in the lung - Regulation by oxygen through a kinetic mechanism [J].
Dweik, RA ;
Laskowski, D ;
Abu-Soud, HM ;
Kaneko, FT ;
Hutte, R ;
Stuehr, DJ ;
Erzurum, SC .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (03) :660-666
[8]   Nitric oxide regulates the aggregation of stimulated human neutrophils [J].
Forslund, T ;
Nilsson, HM ;
Sundqvist, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 274 (02) :482-487
[9]   The biology of cell locomotion within three-dimensional extracellular matrix [J].
Friedl, P ;
Bröcker, EB .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2000, 57 (01) :41-64
[10]   UROKINASE RECEPTOR AND COLORECTAL-CANCER SURVIVAL [J].
GANESH, S ;
SIER, CFM ;
HEERDING, MM ;
GRIFFIOEN, G ;
LAMERS, CBHW ;
VERSPAGET, HW .
LANCET, 1994, 344 (8919) :401-402