ras-induced neoplastic transformation and sensitivity to tumor necrosis factor

Tumor necrosis factor (TNF) is toxic to many tumor cells but not to normal cells. We previously reported that transfection of TNF-resistant C3H10T1/2 fibroblasts with a mutant Ha-ras oncogene induced tumorigenicity as well as TNF sensitivity. To investigate the relationship between tumorigenic transformation and TNF sensitivity, we isolated TNF-resistant revertants from Ha-ras transformed TNF-sensitive cells and analyzed them for p21 expression and tumorigenic potential. The TNF-resistant cells expressed the same amount of mutant p21 as TNF-sensitive cells and retained their tumorigenic potential. In fact, TNF-resistant cells were more tumorigenic than TNF-sensitive cells. These results suggest that mutant p21 expression is directly associated with tumorigenic transformation, while acquisition of TNF sensitivity is incidental to the process of neoplastic transformation. It is possible, however, that ras-induced TNF sensitivity and transformation are regulated by different effector molecules downstream of Ras.