The ability of versican to simultaneously cause apoptotic resistance and sensitivity.
Expression of the extracellular matrix proteoglycan versican is associated with more than 10 types of cancers, often being secreted by stromal cells in response to tumor signals. Previous work in our lab has shown that overexpression of the V1 versican isoform in cultured fibroblasts (V1 cells) increases both proliferation and apoptotic resistance. We show here that V1 cells induced tumor formation in nude mice and that, in keeping with previously shown apoptotic resistance, V1 cells have down-regulated Fas mRNA and protein levels. Unexpectedly, however, V1 cells were found to be sensitized to a wide range of cytotoxic agents. This combination of selective apoptotic resistance and sensitivity is often seen in cancer cells. V1 cells were also shown to have high resting levels of p53 and murine double minute-2 proteins, correlating with apoptotic sensitivity. Treatment with UV radiation induced p21 expression in vector-transfected cells but not in V1 cells. As p21 induces cell cycle arrest and inhibits apoptosis, its loss in V1 cells, coupled with high resting levels of proapoptotic p53, may be at least partially involved in their premature death following cytotoxic treatment. This study further supports the importance of versican in cancer cell biology and the complexity of apoptosis regulation.
LaPierre
David P
DP
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Lee
Daniel Y
DY
Li
Sen-Zhu
SZ
Xie
Yi-Zhen
YZ
Zhong
Ling
L
Sheng
Wang
W
Deng
Zhaoqun
Z
Yang
Burton B
BB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D014466:Ultraviolet Rays; D053675:Versicans / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
D016159:Tumor Suppressor Protein p53; C508323:Vcan protein, mouse; D019014:fas Receptor; D053675:Versicans; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2