Cancer metabolism gets physical

DelNero, Peter; Hopkins, Benjamin D.; Cantley, Lewis C.; Fischbach, Claudia

doi:10.1126/scitranslmed.aaq1011

Cited by 37 publications

(19 citation statements)

References 52 publications

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“…4 D, E and Figure S5A, B ). It is well-established that metabolic reprogramming has been regarded as a core hallmark of cancer, which sustains rapid proliferation and survival of cancer cells [ 8 , 16 ]. Our recent study has identified a novel metabolic reprogramming in HCC due to the loss of glycolytic enzyme aldolase B and targeting this metabolic pathway has potential therapeutic implications [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

et al. 2020

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The well-documented anticarcinogenic properties of natural polyphenolic proanthocyanidins (OPC) have been primarily attributed to their antioxidant and anti-inflammatory potency. Emerging evidence suggests that OPC may target canonical oncogenic pathways, including PI3K/AKT; however, the underlying mechanism and therapeutic potential remain elusive. Here we identify that proanthocyanidin B2 (OPC–B2) directly binds and inhibits AKT activity and downstream signalling, thereby suppressing tumour cell proliferation and metabolism in vitro and in a xenograft and diethyl-nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) mouse models. We further find that OPC-B2 binds to the catalytic and regulatory PH domains to lock the protein in a closed conformation, similar to the well-studied AKT allosteric inhibitor MK-2206. Molecular docking and dynamic simulation suggest that Lys297 and Arg86 are critical sites of OPC-B2 binding; mutation of Lys297 or Arg86 to alanine completely abolishes the antitumor effects of OPC-B2 but not MK-2206. Together, our study reveals that OPC-B2 is a novel allosteric AKT inhibitor with potent anti-tumour efficacy beyond its antioxidant and anti-inflammatory properties.

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Section: Discussionmentioning

confidence: 99%

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

et al. 2020

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“…The rigid tissue culture polystyrene substrates (3G Pa) elevates cytoskeletal tension and chronically activates HSF1, regardless of oncogene-transformation, and this effect obscures any comparative 30 measurements of mitochondrial function in normal and oncogene-transformed cells. Instead, prudent use of model systems with biomimetic properties (physically and chemically similar to the relevant biological system) are needed to uncover oncogene driven alterations in mitochondrial metabolism (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…We thank the following people for their support and advice: Diane 45 Barber and Yi Liu, provided advice and reagents pertaining to SLC9A1 and pH regulation. Milos Simic, generated the constitutively active HSF1.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Adhesion-mediated mechanosignaling forces mitohormesis

Tharp

Higuchi‐Sanabria

Timblin³

et al. 2020

Preprint

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Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu regulates mitochondrial function and contributes to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. Extracellular matrix stiffness and cytoskeletal tension are also altered in cancer and in aged tissues. We 5 determined that cytoskeletal tension elicits a mitochondrial stress response that modifies mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Our data indicate that this cytoskeletal tension-induced mitochondrial stress response, termed mitohormesis, adaptively tunes mitochondrial metabolism and facilitates oxidative stress resilience. These findings demonstrate that cytoskeletal 10 tension regulates mitochondrial function and suggests that mechanical forces influence tissue behavior by modulating mitochondrial metabolism.One Sentence Summary: Adhesion-mediated mechanotransduction programs mitochondrial metabolism through an adaptive stress response.Main Text: Nutrient availability, oxygen content, and pH regulate cellular metabolism. 15Extracellular matrix (ECM) stiffness can change cellular metabolism by regulating the levels and/or activity of cytoplasmic enzymes responsive to cytoskeletal polymerization (1, 2). Many aspects of cellular metabolism depend upon the mitochondria, a key metabolic organelle that is structurally altered by physical forces and the cytoskeleton (3-5). Since mitochondrial structure influences mitochondrial function, we sought to 20 determine if ECM stiffness and cytoskeletal tension influence cellular metabolism by regulating mitochondrial structure and function. Cytoskeletal tension alters mitochondrial structure and functionTo explore associations between ECM stiffness and mitochondrial structure, we examined the mitochondrial morphology of nonmalignant human mammary epithelial 25 cells (MECs; MCF10A) cultured for 24 hours on polyacrylamide hydrogel gels (PA-gel) ranging in elasticity (stiffness) between normal breast stroma (400 Pa) and breast tumors (6k -60k Pa) (6, 7) (tissue culture polystyrene ~3G Pa). MECs cultured on this range of PA-gel elasticities displayed a variety of mitochondrial morphologies, ranging from thin interconnected filaments (400 Pa), to thickened filaments (6k Pa), and then ~300 nM 30 diameter fragments with toroidal shapes (60k Pa) ( Fig.1A and S1A-B). Cells respond to ECM stiffness by ligating ECM adhesion receptors that induce Rho-GTPase-dependent cytoskeletal remodeling and increase actomyosin tension through type-II myosins (8). Pharmacological inhibition of Rho-associated protein kinase (ROCK) with Y27632 or type-II myosins with blebbistatin, reduced the prevalence of the thick toroidal 35 mitochondrial fragments in MECs plated on the stiffest ECM PA-gels (Fig.1A). These data indicate that mitochondrial structure is sensitive to cytoskeletal tension generated in response to stiffness of the ext...

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“…Numerous microenvironmental factors affect cancer cell metabolism (Anastasiou, 2017; Bi et al, 2018; Muir et al, 2018; Wolpaw and Dang, 2018), including the presence of stromal cells (Lyssiotis and Kimmelman, 2017; Morandi et al, 2016), tumor acidity (Corbet and Feron, 2017; Persi et al, 2018), extracellular matrix properties (DelNero et al, 2018; Tung et al, 2015) and tumor nutrient levels (Muir and Vander Heiden, 2018). In particular, environmental nutrient availability is an important regulator of cancer cell metabolism (Cantor et al, 2017; Muir et al, 2017; Schug et al, 2015; Tardito et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Sullivan

Danai

Lewis

et al. 2019

eLife

365

345

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Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

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Cancer metabolism gets physical

Cited by 37 publications

References 52 publications

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

Adhesion-mediated mechanosignaling forces mitohormesis

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

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