Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1.
The squamous cell carcinoma antigen (SCC Ag) is a tumour-associated protein and a member of the serine protease inhibitor (serpin) family. The SCC Ag has been used as a serologic tumour marker for SCC progression, and its elevated serum levels are a risk factor for disease relapse. However, the biologic significance of this intracytoplasmic protein in cancer cells remains unknown. In this report, we demonstrated that apoptosis induced by 7-ethyl-10-hydroxycamptothecin, tumour necrosis factor-alpha (TNF-alpha) or interleukin (IL)-2-activated natural killer (NK) cells was significantly inhibited in tumour cells transduced with the SCC Ag-1 cDNA, as compared to control cells in vitro. Also, inhibition of the SCC Ag-1 expression in tumour cells by transfection of antisense SCC Ag-1 cDNA was accompanied by significantly increased sensitivity of these cells to apoptosis induced by etoposide or TNF-alpha. The mechanism of protection of tumour cells from apoptosis involved inhibition of caspase-3 activity and/or upstream proteases. In vivo, tumour cells overexpressing the SCC Ag-1 formed significantly larger tumours in nude mice than the SCC Ag-1-negative controls. Thus, overexpression of the SCC Ag-1, a member of the serpin family, in human cancer cells contributed to their survival by mediating protection from drug-, cytokine- or effector cell-induced apoptosis.
Suminami
Y
Y
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, PA 15213, USA.
Nagashima
S
S
Vujanovic
N L
NL
Hirabayashi
K
K
Kato
H
H
Whiteside
T L
TL
D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000276:immunology; D017931:DNA Primers; D006258:Head and Neck Neoplasms / Q000276:immunology; D006801:Humans; D015843:Serpins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000951:Antigens, Neoplasm; D017931:DNA Primers; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; C051072:squamous cell carcinoma-related antigen