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Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome

100%

Mrówka P., Głodkowska E., Młynarczuk-Biały I., Biały Ł., Kuckelkorn U., Nowis D., Makowski M., Legat M., Gołąb J.

2008

vol. 55

issue 1

75-84

Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-γ) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-γ agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.

Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells.

75%

Rattan S. I. S., Gonzalez-Dosal R., Nielsen E. R., Kraft D. C., Weibel J., Kahns S.

vol. 51

issue 2

481-492

Since aging is primarily the result of a failure of maintenance and repair mechanisms, various approaches are being developed in order to stimulate these pathways and modulate the process of aging. One such approach, termed hormesis, involves challenging cells and organisms by mild stress that often results in anti-aging and life prolonging effects. In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilisation kinetics, and the proteomic analysis of patterns of proteins synthesised and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro. Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer's disease, Parkinson's disease, cataracts and osteoporosis.

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2 Acta Biochimica Polonica

1 2008

1 2004

1 Biały Ł.

1 Gonzalez-Dosal R.

1 Gołąb J.

1 Głodkowska E.

1 Kahns S.

1 Kraft D. C.

1 Kuckelkorn U.

1 Legat M.

1 Makowski M.

1 Mrówka P.

1 Młynarczuk-Biały I.

1 Nielsen E. R.

1 Nowis D.

1 Rattan S. I. S.

1 Weibel J.

Search results

Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome

Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells.