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Aberrant signaling responses of cells lacking syndecan1 suggest differential metabolic regulation may underlie tumor resistance of syndecan1‐null mice
Author(s) -
Wagner Caroline Ann,
Alexander Caroline
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.794.5
Subject(s) - carcinogenesis , wnt signaling pathway , biology , apoptosis , pi3k/akt/mtor pathway , ampk , population , microbiology and biotechnology , cell growth , cancer research , signal transduction , chemistry , cancer , biochemistry , phosphorylation , medicine , genetics , protein kinase a , environmental health
Caloric restriction (CR) has been shown to inhibit tumorigenesis in a variety of animal models. CR suppresses the action of chemical carcinogens and reduces tumor formation in transgenic mouse models. Several mechanisms thought to underlie the effects of CR have been described. Levels of IGF‐1 are reduced in animals under caloric restriction, and animals show increased insulin sensitivity. CR reduces cell proliferation, enhances apoptosis, upregulates activation of AMPK (a low energy sensor) and downregulates mTOR signaling (a nutrient responsive pathway). Syndecan1 (Sdc1), a heparan sulfate proteoglycan, has been shown to be important for tumor formation. Mice lacking Sdc1 are protected from tumorigenesis in response to a chemical carcinogen and ectopic Wnt‐1 expression. To elucidate the mechanism of tumor resistance we study mammary epithelial cells (MECs). Sdc1‐null MECs in vitro show decreased population expansion in response to Wnt3A and insulin compared to wild‐type populations. Analysis of cell kinetics demonstrates that Sdc1‐null populations undergo reduced proliferation and increased apoptosis. Western blot analysis shows increased activation of AMPK in Sdc1‐null MECs. The characteristics we observe in Sdc1‐null mice and tissues suggest that metabolic alterations may be underlying the tumor resistance of Sdc1‐null mice. This research is supported by an RO1 grant and a DOD Era of Hope grant.