Pharmacological mimicking of caloric restriction elicits epigenetic reprogramming of differentiated cells to stem-like self-renewal states.
Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and underexpressed in response to pharmacological mimicking of caloric restriction. By following this methodological approach, we recently obtained data fitting a model in which, in response to chronic impairment of cellular bioenergetics imposed by metformin-induced mitochondrial uncoupling as assessed by the phosphorylation state of cAMP-response element binding protein (CREB), tumor cells can retrogress from a differentiated state to a more CD44(+) stem-like primitive state epigenetically governed by the Polycomb-group suppressor BMI1-a crucial "stemness" gene involved in the epigenetic maintenance of adult stem cells. These findings might provide a novel molecular avenue to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.
Catalan Institute of Oncology, Girona, Catalonia, Spain.
Cristina
C
Oliveras-Ferraros
Alejandro
A
Vazquez-Martin
Javier A
JA
Menendez
D000375:Aging / Q000502:physiology; D031204:Caloric Restriction / Q000379:methods*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000235:genetics*; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism