CELLULAR FACTORS MAY ENABLE SQUAMOUS CARCINOMA-CELLS TO OVERCOME TGF-BETA-MEDIATED REPRESSION OF CDK2 ACTIVITY

Cell lines developed from head and neck squamous cell carcinomas exhib it variable responses to the negative regulatory effects of transformi ng growth factor beta (TGF beta) on cell growth. To analyse the effect s of TGF beta on regulators of cell cycle progression, we characterise d cell lines derived from head and neck squamous cell carcinoma (HNSCC ) for their biological sensitivities to TGF beta, growth inhibition, t hen examined the effects of TGF beta treatment on the expression and a ctivity of cyclin dependent kinases (CDKs) and inhibitors of these kin ases. Western blot analysis of cell lysates from untreated or TGF beta -treated cultures showed no alterations in expression of CDK2, CDK4, C DK6 or cyclin E in cell lines which were either sensitive (HaCaT, HN6) or refractory (HN12, HN30) to the growth-inhibitory effects of TGF be ta. However, treatment of cells with TGF beta resulted in a several fo ld increase in cellular levels of p21 (WAF1/Cip1), irrespective of bio logical response. Immune complex in vitro kinase assays demonstrated t hat the activity of CDK2 was inhibited by exposure to ligand in each c ase, confirming that a TGF beta signalling pathway which regulates kin ase activity was intact in these cell lines. The data suggest that cel lular factors expressed in HN12 and HN30 enable these cells to overrid e TGF beta-mediated inhibition of CDK2 activity and allow cell cycle p rogression. This may represent an important mechanism which allows cel ls to evade growth arrest during malignant progression. (C) 1998 Elsev ier Science Ltd. All rights reserved.