scholarly journals TSC-Insensitive Rheb Mutations Induce Oncogenic Transformation Through a Combination of Hyperactive mTORC1 Signalling and Metabolic Reprogramming

2020 ◽  
Author(s):  
Jianling Xie ◽  
Stuart P. De Poi ◽  
Sean J. Humphrey ◽  
Leanne K. Hein ◽  
John Bruning ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tuberous Sclerosis Complex ◽  
Tumour Growth ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Mechanistic Target Of Rapamycin ◽  
Differential Interaction ◽  
Oncogenic Pathways ◽  
Important Regulator

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes by causing hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, Tuberous Sclerosis Complex.We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth, proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving metabolic reprogramming and an increased rate of glycolysis, while Rheb-E40K regulates the translation factor eEF2 and autophagy, likely through a differential interaction with AMPK.Our findings suggest that unique ‘bespoke’ combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.

scholarly journals PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

2016 ◽  
Vol 40 (3-4) ◽  
pp. 757-769 ◽  
Author(s):  
Li Zhang ◽  
Guozhan Jia ◽  
Binya Shi ◽  
Guanqun Ge ◽  
Hongbin Duan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Hepg2 Cells ◽  
Tumour Growth ◽  
Xenograft Model ◽  
Tumour Suppressor ◽  
Poor Overall Survival

Background: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC). Methods: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. Results: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin. Conclusions: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

scholarly journals Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 499 ◽  
Author(s):  
Tasleem Arif ◽  
Avijit Paul ◽  
Yakov Krelin ◽  
Anna Shteinfer-Kuzmine ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Lung Cancer ◽  
Cell Differentiation ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tumour Growth ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Residual Tumour ◽  
Cancer Cell Metabolism

Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual “tumour” showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.

scholarly journals In vivo genetic dissection of tumor growth and the Warburg effect

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Cheng-Wei Wang ◽  
Arunima Purkayastha ◽  
Kevin T Jones ◽  
Shivani K Thaker ◽  
Utpal Banerjee
Keyword(s):  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Feedback Signal ◽  
Vegf Receptor ◽  
Genetic Dissection ◽  
Oncogenic Pathways ◽  
Genes Encoding ◽  
The Warburg Effect

A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr). This causes activation of multiple oncogenic pathways including Ras, PI3K/Akt, Raf/ERK, Src and JNK. Together this network of genes stabilizes Hifα (Sima) that in turn, transcriptionally up-regulates many genes encoding glycolytic enzymes. Collectively, this network of genes also causes inhibition of pyruvate dehydrogenase (PDH) activity resulting in diminished ox-phos levels. The high ROS produced during this process functions as a feedback signal to consolidate this metabolic reprogramming.

scholarly journals Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 121 ◽  
Author(s):  
Meng Li ◽  
Ling Wang ◽  
Yijin Wang ◽  
Shaoshi Zhang ◽  
Guoying Zhou ◽  
...  
Keyword(s):  
Cell Growth ◽  
Liver Cancer ◽  
Tumor Cell ◽  
Tumor Formation ◽  
Mitochondrial Fusion ◽  
Metabolic Reprogramming ◽  
Mitochondrial Functions ◽  
Tumor Organoids

Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.

scholarly journals Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression

Cancers ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 5 ◽  
Author(s):  
Ellie Rad ◽  
James Murray ◽  
Andrew Tee
Keyword(s):  
Cell Growth ◽  
Cancer Progression ◽  
Growth Control ◽  
Protein Translation ◽  
Metastatic Potential ◽  
Metabolic Reprogramming ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin ◽  
Metabolic Transformation ◽  
Normal Human

Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell growth by enhancing the efficiency of protein translation. Research in the last decade has revealed that mTOR’s role in promoting cell growth is much more multifaceted. While mTOR is necessary for normal human physiology, cancer cells take advantage of mTOR signalling to drive their neoplastic growth and progression. Oncogenic signal transduction through mTOR is a common occurrence in cancer, leading to metabolic transformation, enhanced proliferative drive and increased metastatic potential through neovascularisation. This review focuses on the downstream mTOR-regulated processes that are implicated in the “hallmarks” of cancer with focus on mTOR’s involvement in proliferative signalling, metabolic reprogramming, angiogenesis and metastasis.

scholarly journals Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex

2017 ◽  
Vol 214 (3) ◽  
pp. 681-697 ◽  
Author(s):  
Ebru Ercan ◽  
Juliette M. Han ◽  
Alessia Di Nardo ◽  
Kellen Winden ◽  
Min-Joon Han ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Tissue Growth ◽  
Mechanistic Target Of Rapamycin ◽  
Genetic Deletion ◽  
Oligodendrocyte Development ◽  
Therapeutic Avenue

Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non–cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.

miR-324-5p upregulation potentiates resistance to cisplatin by targeting FBXO11 signalling in non-small cell lung cancer cells

2019 ◽  
Vol 166 (6) ◽  
pp. 517-527 ◽  
Author(s):  
Zhichang Ba ◽  
Yufei Zhou ◽  
Zhaoyang Yang ◽  
Jianyu Xu ◽  
Xiushi Zhang
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Molecular Basis ◽  
Tumour Growth ◽  
Small Cell ◽  
Mirna Signature ◽  
Small Cell Lung ◽  
Drug Naïve

Abstract Dysregulation of microRNAs (miRNAs) plays a key role during the pathogenesis of chemoresistance in lung cancer (LCa). Previous study suggests that miR-324-5p may serve as a unique miRNA signature for LCa, but its role and the corresponding molecular basis remain largely explored. Herein, we report that miR-324-5p expression was significantly increased in cisplatin (CDDP)-resistant LCa tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in LCa patients. miR-324-5p was further shown to impact CDDP response: Ectopic miR-324-5p expression in drug-naïve LCa cells was sufficient to attenuate sensitivity to CDDP and to confer more robust tumour growth in CDDP-challenged nude mice. Conversely, ablation of miR-324-5p expression in resistant cells effectively potentiated CDDP-suppressed cell growth in vitro and in vivo. Using multiple approaches, we further identified the tumour suppressor FBXO11 as the direct down-stream target of miR-324-5p. Stable expression of FBXO11 could abrogate the pro-survival effects of miR-324-5p in CDDP-challenged LCa cells. Together, these findings suggest that miR-324-5p upregulation mediates, at least partially, the CDDP resistance by directly targeting FBXO11 signalling in LCa cells. In-depth elucidation of the molecular basis underpinning miR-324-5p action bears potential implications for mechanism-based strategies to improve CDDP responses in LCa.

scholarly journals MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Shuhua Zhao ◽  
Xiaohong Zhang ◽  
Yuan Shi ◽  
Lu Cheng ◽  
Tingting Song ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Glucose Metabolism ◽  
Clinical Significance ◽  
Metabolic Reprogramming ◽  
Biological Functions ◽  
Close Link ◽  
Mesenchymal Transition

Abstract Background Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC). Methods The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses. Results MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predicts poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to-mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells. Conclusions MIEF2 plays a critical role in the progression of OC and may serve as a valuable prognostic biomarker and therapeutic target in the treatment of this malignancy.

scholarly journals MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

2020 ◽  
Author(s):  
Shuhua Zhao ◽  
Yuan Shi ◽  
Xiaohong Zhang ◽  
Lu Cheng ◽  
Tingting Song ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Glucose Metabolism ◽  
Clinical Significance ◽  
Metabolic Reprogramming ◽  
Biological Functions ◽  
Close Link ◽  
Mesenchymal Transition

Abstract Background: Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC). Methods: The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses. Results: MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predictes poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to -mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells. Conclusions: MIEF2 play a critical role in the promotion of OC progression and may serve as a valuable prognostic biomarker and therapeutic target in treatment of this malignancy.

A growing role for mTOR in promoting anabolic metabolism

2013 ◽  
Vol 41 (4) ◽  
pp. 906-912 ◽  
Author(s):  
Jessica J. Howell ◽  
Stéphane J.H. Ricoult ◽  
Issam Ben-Sahra ◽  
Brendan D. Manning
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Nucleic Acids ◽  
Tumour Growth ◽  
Building Blocks ◽  
Mechanistic Target Of Rapamycin ◽  
Metabolic Functions ◽  
Molecular Events ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1

mTOR [mammalian (or mechanistic) target of rapamycin] is a protein kinase that, as part of mTORC1 (mTOR complex 1), acts as a critical molecular link between growth signals and the processes underlying cell growth. Although there has been intense interest in the upstream mechanisms regulating mTORC1, the full repertoire of downstream molecular events through which mTORC1 signalling promotes cell growth is only recently coming to light. It is now recognized that mTORC1 promotes cell growth and proliferation in large part through the activation of key anabolic processes. Through a variety of downstream targets, mTORC1 alters cellular metabolism to drive the biosynthesis of building blocks and macromolecules fundamentally essential for cell growth, including proteins, lipids and nucleic acids. In the present review, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth and proliferation. As mTORC1 is aberrantly activated in a number of tumour syndromes and up to 80% of human cancers, we also discuss the importance of this mTORC1-driven biosynthetic programme in tumour growth and progression.

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