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PIII‐31
Author(s) -
Lin J. E.,
Gibbons A. V.,
Farber J. L.,
Schulz S.,
Pitari G. M.,
Waldman S. A.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.239
Subject(s) - mitochondrial biogenesis , mitochondrion , microbiology and biotechnology , carcinogenesis , biology , biogenesis , signal transduction , cytosol , cancer research , biochemistry , cancer , genetics , gene , enzyme
BACKGROUND Mitochondria provide energy in the form of ATP which supports biochemical processes and biological functions in cells. Mitochondrial insufficiency is related to several pathological processes, including ischemia‐induced injury and tumorigenesis. Although guanylyl cyclases and cyclic GMP signaling regulate mitochondrial function in many tissues, the relationship between the tumor suppressor GCC and mitochondrial biogenesis in intestinal epithelial cells remains undefined. METHODS The relationship between GCC signaling and mitochondrial biogenesis was examined in vitro in NCM460 normal human colonocytes and the human colon carcinoma cell lines T84, Caco‐2 and SW480, and in vivo in GCC −/− mice. Mitochondrial biogenesis was measured by qPCR, qRT‐PCR, and immunoblot analysis. Mitochondrial function was quantified by the MTT assay. RESULTS Ligand activation of GCC and accumulation of cGMP induced mitochondrial biogenesis in normal and neoplastic intestinal epithelial cells. Indeed, GCC signaling increased the number and function of mitochondria in those cells. Moreover, intestinal epithelial cells of GCC −/− mice exhibit significantly reduced mitochondrial content compared to GCC +/+ mice. CONCLUSIONS GCC is a tumor suppressor whose signaling is coupled with mitochondrial biogenesis in intestine. In colorectal tumorigenesis, interruption of GCC signaling and the associated dysregulation of mitochondrial activity may play a role in disease initiation and/or progression. Clinical Pharmacology & Therapeutics (2005) 79 , P66–P66; doi: 10.1016/j.clpt.2005.12.239