Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells.
BACKGROUND
Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1) and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells.


RESULTS
DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated complement protein. Under complement C1q- or C6-free conditions, WOX1 and ERK were mainly present in the cytoplasm without phosphorylation, whereas phosphorylated JNK1 was greatly accumulated in the nuclei. Exogenous C1q rapidly restored the WOX1 activation (with Tyr33 phosphorylation) in less than 2 hr. Without serum complement C9, p53 became activated, and hyaluronan (HA) reversed the effect. Under C6-free conditions, HA induced activation of STAT3, an enhancer of metastasis. Notably, exogenous C1q significantly induced apoptosis of WOX1-overexpressing DU145 cells, but not vehicle-expressing cells. A dominant negative and Y33R mutant of WOX1 blocked the apoptotic effect. C1q did not enhance p53-mediated apoptosis. By total internal reflection fluorescence (TIRF) microscopy, it was determined that C1q destabilized adherence of WOX1-expressing DU145 cells by partial detaching and inducing formation of clustered microvilli for focal adhesion particularly in between cells. These cells then underwent shrinkage, membrane blebbing and death. Remarkably, as determined by immunostaining, benign prostatic hyperplasia and prostate cancer were shown to have a significantly reduced expression of tissue C1q, compared to age-matched normal prostate tissues.


CONCLUSIONS
We conclude that complement C1q may induce apoptosis of prostate cancer cells by activating WOX1 and destabilizing cell adhesion. Downregulation of C1q enhances prostate hyperplasia and cancerous formation due to failure of WOX1 activation.
Hong
Qunying
Q
Guthrie Research Institute, Laboratory of Molecular Immunology, Sayre, PA, USA.
Sze
Chun-I
CI
Lin
Sing-Ru
SR
Lee
Ming-Hui
MH
He
Ruei-Yu
RY
Schultz
Lori
L
Chang
Jean-Yun
JY
Chen
Shean-Jen
SJ
Boackle
Robert J
RJ
Hsu
Li-Jin
LJ
Chang
Nan-Shan
NS
D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015922:Complement C1q / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015922:Complement C1q; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human