Creatine kinase brain overexpression protects colorectal cells from various metabolic and non‐metabolic stresses

Mooney, Steven M.; Rajagopalan, Krithika; Williams, Brenten H.; Zeng, Yu; Christudass, Christhunesa S.; Li, Youqiang; Yin, Bo; Kulkarni, Prakash; Getzenberg, Robert H.

doi:10.1002/jcb.23020

Cited by 38 publications

(32 citation statements)

References 24 publications

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“…Second, chronic inflammation associated with IBD is a major risk factor for colitis-associated cancer. A number of studies have now identified reduced levels of CKB in colonic tumors (35,36), whereas studies using dominant negative CKB mutants have defined a correlation with molecular markers of epithelial-to-mesenchymal transition in colon cancer cells (37). Taken together, these observations provide a compelling argument for Cr supplementation as an adjuvant therapy to promote epithelial restitution and ameliorate mucosal inflammation via enhanced cellular energetics.…”

Section: Discussionmentioning

confidence: 99%

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Glover

Bowers²,

Saeedi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

115

134

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Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.epithelial junctions | energy metabolism | actomyosin | IBD

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Section: Discussionmentioning

confidence: 99%

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Glover

Bowers²,

Saeedi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

115

134

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“…Creatine has a protective role against metabolic and hypoxic cell death in vitro (19)(20)(21). To examine cell death in vivo, colons from Gatm c/c and wild-type mice were examined for cell death by TUNEL staining on the fourth day of DSS treatment.…”

Section: Increased Cell Death and Decreased Proliferation In Gatm C/cmentioning

confidence: 99%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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“…Mesenchymal cells attach more strongly to the extracellular matrix (ECM) and are able to act as path generators by secreting matrix metalloproteinases (MMPs) 21. MMPs degrade the extracellular matrix (ECM) and disrupt cell-cell and cell-ECM interactions, thereby promoting migration and invasion 22.…”

Section: Emt In Pcamentioning

confidence: 99%

Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

et al. 2016

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A striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men.

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Creatine kinase brain overexpression protects colorectal cells from various metabolic and non‐metabolic stresses

Cited by 38 publications

References 24 publications

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Creatine maintains intestinal homeostasis and protects against colitis

Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

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