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Studies on human fibroblasts have led to viewing senescence as a barrier against tumorigenesis. Using keratinocytes, we show here that partially transformed and tumorigenic cells systematically and spontaneously emerge from senescent cultures. We show that these emerging cells are generated from senescent cells, which are still competent for replication, by an unusual budding-mitosis mechanism. We further present data implicating reactive oxygen species that accumulate during senescence as a potential mutagenic motor of this post-senescence emergence. We conclude that senescence and its associated oxidative stress could be a tumor-promoting state for epithelial cells, potentially explaining why the incidence of carcinogenesis dramatically increases with advanced age.

Cyclooxygenase-2 (COX-2) is an inducible enzyme of the prostaglandin biosynthesis pathway. It is involved in many stress responses, and its activity can produce oxidative damage, suggesting it could participate in senescence. In this study, COX-2 expression is shown to increase during senescence of normal human dermal or prostatic fibroblasts, and the ensuing prostaglandin E(2) (PGE(2)) production to increase about 10-fold. Enhancing this COX-2 activity by supplying exogenous arachidonic acid accelerates the occurrence of the major markers of senescence, cell-size increase, spreading, senescence-associated-beta-galactosidase (SA-beta-Gal) activity and growth plateau. Conversely, blocking this COX-2 activity with the specific inhibitor NS398 partially inhibited the occurrence of these markers. COX-2 expression and PGE(2) production are also increased about 10-fold during both NF-kappaB- or H(2)O(2)-induced senescence. Using NS398 or small interferent RNA specifically targeting COX-2 attenuated the appearance of the SA-beta-Gal activity and growth arrest in both stress situations. Taken together, these findings indicate that COX-2 is highly up-regulated during both normal and stress-induced fibroblast senescence and contributes to the establishment of the senescent characteristics.