In Scarcity and Abundance: Metabolic Signals Regulating Cell Growth

Although nutrient availability is a major driver of cell growth, and continuous adaptation to nutrient supply is critical for the development and survival of all organisms, the molecular mechanisms of nutrient sensing are only beginning to emerge. Here, we highlight recent advances in the field of nutrient sensing and discuss arising principles governing how metabolism might regulate growth-promoting pathways. In addition, we discuss signaling functions of metabolic enzymes not directly related to their metabolic activity.

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Faculty Opinions recommendation of Reconstruction of ancestral metabolic enzymes reveals molecular mechanisms underlying evolutionary innovation through gene duplication.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717970129.793468743 ◽

2013 ◽

Author(s):

Matthew Mulvey ◽

Travis Wiles

Keyword(s):

Gene Duplication ◽

Molecular Mechanisms ◽

Metabolic Enzymes ◽

Evolutionary Innovation

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Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

Cancer Biomarkers ◽

10.3233/cbm-210189 ◽

2021 ◽

pp. 1-9

Author(s):

Huan Guo ◽

Baozhen Zeng ◽

Liqiong Wang ◽

Chunlei Ge ◽

Xianglin Zuo ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Lung Cancer Cells ◽

Invasion And Migration ◽

And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

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Exploring the Intracrine Functions of VEGF-A

Biomolecules ◽

10.3390/biom11010128 ◽

2021 ◽

Vol 11 (1) ◽

pp. 128

Author(s):

Sophie Wiszniak ◽

Quenten Schwarz

Keyword(s):

Cell Growth ◽

Molecular Mechanisms ◽

Direct Action ◽

Cancer Therapeutics ◽

Cell Types ◽

Vascular Endothelial ◽

Signalling Molecule ◽

Endothelial Growth Factor ◽

Important Signalling Molecule ◽

Vegf Signalling

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.

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LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽

10.1038/s41389-021-00306-1 ◽

2021 ◽

Vol 10 (2) ◽

Author(s):

Yu Geon Lee ◽

Hui Won Kim ◽

Yeji Nam ◽

Kyeong Jin Shin ◽

Yu Jin Lee ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Survival ◽

Cancer Cell ◽

Stress Responses ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Mitochondrial Matrix ◽

Mitochondrial Functions ◽

Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

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Cellular modulation by the elasticity of biomaterials

Journal of Materials Chemistry B ◽

10.1039/c5tb02077h ◽

2016 ◽

Vol 4 (1) ◽

pp. 9-26 ◽

Cited By ~ 51

Author(s):

Fengxuan Han ◽

Caihong Zhu ◽

Qianping Guo ◽

Huilin Yang ◽

Bin Li

Keyword(s):

Extracellular Matrix ◽

Cell Fate ◽

Molecular Mechanisms ◽

Matrix Elasticity ◽

Recent Advances

The elasticity of the extracellular matrix has been increasingly recognized as a dominating factor of cell fate and activities. This review provides an overview of the general principles and recent advances in the field of matrix elasticity-dependent regulation of a variety of cellular activities and functions, the underlying biomechanical and molecular mechanisms, as well as the pathophysiological implications.

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Acetone-desiccated Adult Tissues as a Source of Cell Growth-promoting Extracts

Science ◽

10.1126/science.105.2727.369-b ◽

1947 ◽

Vol 105 (2727) ◽

pp. 369-370

Author(s):

E. Margoliash

Keyword(s):

Cell Growth ◽

Adult Tissues ◽

Growth Promoting

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MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x14973124850905 ◽

2018 ◽

Vol 26 (3) ◽

pp. 385-400 ◽

Cited By ~ 14

Author(s):

Dandan Li ◽

Changjun He ◽

Junfeng Wang ◽

Yanbo Wang ◽

Jianlong Bu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Feedback Loop ◽

Molecular Mechanisms ◽

Small Cell ◽

Luciferase Reporter ◽

Small Cell Lung

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

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Recent Advances in Understanding Werner Syndrome

F1000Research ◽

10.12688/f1000research.12110.1 ◽

2017 ◽

Vol 6 ◽

pp. 1779 ◽

Cited By ~ 36

Author(s):

Raghavendra A. Shamanna ◽

Deborah L. Croteau ◽

Jong-Hyuk Lee ◽

Vilhelm A. Bohr

Keyword(s):

Dna Repair ◽

Stem Cell ◽

Genome Stability ◽

Werner Syndrome ◽

Genetic Disorder ◽

Accelerated Aging ◽

Nutrient Sensing ◽

Telomere Maintenance ◽

Telomere Attrition ◽

Recent Advances

Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

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