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Type III TGF-? receptor enhances colon cancer cell migration and anchorage-independent growth.

ABSTRACT: The type III TGF-? receptor (T?RIII or betagylcan) is a TGF-? superfamily coreceptor with emerging roles in regulating TGF-? superfamily signaling and cancer progression. Alterations in TGF-? superfamily signaling are common in colon cancer; however, the role of T?RIII has not been examined. Although T?RIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, T?RIII messenger RNA expression is not significantly altered and T?RIII expression is more frequently increased at the protein level, suggesting a distinct role for T?RIII in colon cancer. Increasing T?RIII expression in colon cancer model systems enhanced ligand-mediated phosphorylation of p38 and the Smad proteins, while switching TGF-? and BMP-2 from inhibitors to stimulators of colon cancer cell proliferation, inhibiting ligand-induced p21 and p27 expression. In addition, increasing T?RIII expression increased ligand-stimulated anchorage-independent growth, a resistance to ligand- and chemotherapy-induced apoptosis, cell migration and modestly increased tumorigenicity in vivo. In a reciprocal manner, silencing endogenous T?RIII expression decreased colon cancer cell migration. These data support a model whereby T?RIII mediates TGF-? superfamily ligand-induced colon cancer progression and support a context-dependent role for T?RIII in regulating cancer progression.

SUBMITTER: Gatza CE

PROVIDER: S-EPMC3156666 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Type III TGF-β receptor enhances colon cancer cell migration and anchorage-independent growth.

Gatza Catherine E CE Holtzhausen Alisha A Kirkbride Kellye C KC Morton Allyson A Gatza Michael L ML Datto Michael B MB Blobe Gerard C GC

Neoplasia (New York, N.Y.) 20110801 8

The type III TGF-β receptor (TβRIII or betagylcan) is a TGF-β superfamily coreceptor with emerging roles in regulating TGF-β superfamily signaling and cancer progression. Alterations in TGF-β superfamily signaling are common in colon cancer; however, the role of TβRIII has not been examined. Although TβRIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, TβRIII messenge ...[more]

PMID: 21847367

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Project description:Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.

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Type III TGF-? receptor enhances colon cancer cell migration and anchorage-independent growth.

Publications

Type III TGF-β receptor enhances colon cancer cell migration and anchorage-independent growth.

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