Induction of apoptosis in human replicative senescent fibroblasts.
Cellular senescence is an irreversible growth phase characteristic of normal cells. We have found that human senescent fibroblasts can be induced to undergo programmed cell death (apoptosis) by ceramide, TNF-alpha, or okadaic acid. The most profound effects were induced by TNF-alpha and okadaic acid treatment. In the present study, we also evaluated the contribution of lysosomal activation as a possible mechanism underlying the induction of apoptosis. Four lysosomal enzyme activities were measured: beta-galactosidase, alpha-galactosidase A, beta-glucoronidase, and acid phosphatase. Using an in situ assay, we have found that the activity of beta-galactosidase, which is also a biochemical marker of senescence, is induced in young proliferating fibroblasts following exposure to all three apoptotic inducing agents. The other enzymes were not significantly induced in young fibroblasts following exposure to agents that induce apoptosis. During replicative senescence, three of the four lysosomal enzymes tested (beta-galactosidase, alpha-galactosidase A, and beta-glucoronidase) are constitutively expressed at high levels. TNF-alpha was the only agent that induced lysosomal activity in senescent fibroblasts, of which only alpha-galactosidase A activity was induced. Our studies show that senescent fibroblasts can be induced to undergo apoptosis in a signal-dependent manner. However, the lysosomal enzymes examined do not appear to be correlated with apoptotic induction.
DeJesus
Vimaris
V
Department of Biology, City College of New York, 138th and Convent Avenue, New York, New York 10031, USA.
Rios
Ileana
I
Davis
Claudette
C
Chen
Yengsi
Y
Calhoun
David
D
Zakeri
Zahra
Z
Hubbard
Karen
K
D000135:Acid Phosphatase / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D016922:Cellular Senescence / Q000502:physiology*; D002518:Ceramides / Q000494:pharmacology; D005347:Fibroblasts / Q000502:physiology*; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000519:alpha-Galactosidase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D002518:Ceramides; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D006867:Hydrolases; D000135:Acid Phosphatase; D000519:alpha-Galactosidase; D001616:beta-Galactosidase; D005966:Glucuronidase