Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma

Calvisi, Diego F.; Wang, Chunmei; Ho, Coral; Ladu, Sara; Lee, Susie A.; Mattu, Sandra; Destefanis, G; Delogu, Salvatore; Zimmermann, Antje; Ericsson, Johan; Brozzetti, Stefania; Staniscia, Tommaso; Chen, Xin; Dombrowski, Frank; Evert, Matthias

doi:10.1053/j.gastro.2010.12.006

Cited by 489 publications

(604 citation statements)

References 33 publications

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“…Differential lipid metabolism is an important risk factor in liver cancer [99][100][101]. Accordingly, the expression of stearoyl-CoA desaturase, a membrane protein of the endoplasmic reticulum that catalyzes the formation of monounsaturated fatty acids from saturated fatty acids, was found to be associated with aggressiveness of HCC [100][101][102].…”

Section: Metabolic Alterations In Liver Cancermentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

100

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Section: Metabolic Alterations In Liver Cancermentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

100

104

View full text Add to dashboard Cite

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“…De novo lipogenesis is gradually induced from nontumor liver tissue to liver cancer. Blocking lipogenesis is a potential strategy for targeted therapy of HCC (Calvisi et al ., 2011). Genetic ablation of lipogenic enzymes results in complete inhibition of HCC development in mice with an AKT overexpression background (Li et al ., 2016a).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, actively proliferating cells, particularly tumor cells, have an increased demand for lipids, which largely depends on de novo lipogenesis. Sequencing of HCC tissue and nontumor tissue indicates that the target of SREBP‐1 is generally activated in cancer tissues (Calvisi et al ., 2011). Therefore, SREBP transcriptional activity is crucial for tumor growth, making it a potential therapeutic target (Shao and Espenshade, 2012).…”

Section: Introductionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.

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“…Experimentally, Akt promotes proliferation in a variety of cell and animal models 13 . Akt is frequently induced in human HCC samples, and overexpression of Akt in mouse livers results in tumour development 14,15 . Disruption of the PI3K/Akt axis correlates with HCC growth arrest and/or apoptosis 16 .…”

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confidence: 99%

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

et al. 2015

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G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor b-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-a production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-a production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-a directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.

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Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma

Abstract: Background & Aims-De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in pathogenesis of human hepatocellular carcinoma (HCC).

Cited by 489 publications

References 33 publications

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

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