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 ele vated serum levels are a risk factor for disease relapse. However, the biol ogic 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 interle ukin (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-l expression in tumour cells by transfection of antisense SCC Ag-l cDNA was accompanied by significantl y increased sensitivity of these cells to apoptosis induced by etoposide or TNF-alpha. The mechanism of protection of tumour cells from apoptosis invo lved inhibition of caspase-3 activity and/or upstream proteases, In vivo, t umour cells overexpressing the SCC Ag-l formed significantly larger tumours in nude mice than the SCC Ag-l-negative controls. Thus, overexpression of the SCC Ag-l, a member of the serpin family, in human cancer cells contribu ted to their survival by mediating protection from drug-, cytokine- or effe ctor cell-induced apoptosis, (C) 2000 Cancer Research Campaign.