title: Extracellular matrix regulation of metabolism and implications for tumorigenesis.
abstract: Attachment to extracellular matrix (ECM) is required for the survival and proliferation of normal epithelial cells. Epithelial tumor cells, however, often acquire "anchorage independence," a property that may contribute to their ability to invade and grow in foreign environments. Although apoptosis is the most rapid and effective mechanism that causes the death of matrix-detached cells, it has become apparent that detachment from matrix alters other aspects of cell physiology prior to commitment to cell death and that some of these alterations can lead to cell death under conditions where apoptosis is suppressed. This report provides an overview of death processes that contribute to the death of matrix-detached normal cells and describes mechanisms that confer anchorage independence, with a focus on ECM regulation of cell metabolism. Loss of matrix attachment leads to metabolic stress characterized by reduced nutrient uptake, decreased ATP production, and increased levels of reactive oxygen species (ROS). The decrease in ATP levels is prevented by either constitutive activation of the PI3K/Akt pathway or exogenous antioxidants. Additionally, decreased Erk signaling in matrix-detached cells causes a disproportionate decrease in flux through pyruvate dehydrogenase (PDH), leading to decreased entry of glucose carbons into the citric acid cycle. Interestingly, forced overexpression of a PDH inhibitor suppresses de novo lipogenesis and proliferation, highlighting the importance of mitochondrial metabolism in supplying intermediates for biosynthetic processes required for proliferation. Thus, ECM attachment is a key regulator of cellular metabolism, and alterations in metabolism owing to changes or loss of ECM engagement during tumorigenesis may serve important tumor-suppressive functions.
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: A R
authors: AR
authors: Grassian
authors: J L
authors: JL
authors: Coloff
authors: J S
authors: JS
authors: Brugge
mesh_terms: D000818:Animals; D001343:Autophagy; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species