p53, a novel regulator of lipid metabolism pathways

Goldstein, Ido; Ezra, Osnat; Rivlin, Noa; Molchadsky, Alina; Madar, Shalom; Goldfinger, Naomi; Rotter, Varda

doi:10.1016/j.jhep.2011.08.022

Cited by 91 publications

(76 citation statements)

References 32 publications

(31 reference statements)

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“…This question can be answered by comparing the drug treatment effects on HepG2 cells after p53 knockdown and/or on Hep3B cells after p53 restoration by overexpression. In p53 knockdown studies using cDNA microarray assays to obtain a global analysis of endogenous p53 target genes, it has been shown that only Fas/Apo-1 and TGFb type I receptor (Goldstein et al 2012), cyclin D1 (Lefort et al 2007), or none (Chau et al 2009) is responsive to p53 knockdown. Furthermore, in order to determine whether the differential drug responses between HepG2 and Hep3B cells are dependent on the status of p53 or not, we analyzed the published data of differential responses against drug treatments in HepG2 and Hep3B cells as shown in Table 2.…”

Section: Underlying Mechanisms Responsible For the Differences Betweementioning

confidence: 99%

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Qiu

Xie

et al. 2014

Cytotechnology

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As cellular models for in vitro liver cancer and toxicity studies, HepG2 and Hep3B are the two most frequently used liver cancer cell lines. Because of their similarities they are often treated as the same in experimental studies. However, there are many differences that have been largely over-sighted or ignored between them. In this review, we summarize the differences between HepG2 and Hep3B cell lines that can be found in the literature based on PubMed search. We particularly focus on the differential gene expression, differential drug responses (chemosensitivity, cell cycle and growth inhibition, and gene induction), signaling pathways associated with these differences, as well as the factors in governing these differences between HepG2 and Hep3B cell lines. Based on our analyses of the available data, we suggest that neither HBx nor p53 may be the crucial factor to determine the differences between HepG2 and Hep3B cell lines although HBx regulates the expression of the majority of genes that are differentially expressed between HepG2 and Hep3B. Instead, the different maturation stages in cancer development of the original specimen between HepG2 and Hep3B may be responsible for the differences between them. This review provides insight into the molecular mechanisms underlying the differences between HepG2 and Hep3B and help investigators especially the beginners in the areas of liver cancer research and drug metabolism to fully understand, and thus better use and interpret the data from these two cell lines in their studies.

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Section: Underlying Mechanisms Responsible For the Differences Betweementioning

confidence: 99%

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Qiu

Xie

et al. 2014

Cytotechnology

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“…The p53 is found to be involved in the regulation of cellular metabolic pathways besides its classical tumor suppressive functions, such as glycolysis, OXPHOS, and amino acid metabolism [39][40][41][42][43]. It also plays an important role in lipid and lipoprotein metabolism [44]. Thus it can be assumed that mutant p53 could play a greater role in metabolic reprogramming.…”

Section: Metabolic Remodeling In Relation To Genetic Alterationsmentioning

confidence: 99%

Anticancer Strategy Targeting Mitochondrial Biogenesis in Ovarian Cancer

Uddin¹,

Kim²,

Suh³

et al. 2014

J Cancer Sci Ther

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IntroductionOvarian cancer is the most lethal gynecologic malignancy worldwide typically in the post-menopausal women and 5 th leading cause of death in the United States [1][2][3]. About 80% of women are diagnosed at the advanced-stage of disease and have poor prognosis. The 5-year overall survival rate is 45% or below [4][5][6]. Despite the first complete response after the front-line platinum-based chemotherapeutic drugs [7,8], approximately 25% patients suffer from relapse within 6 months who are thought, by definition, to have a chemoresistance [9][10][11][12]. Combination of platinum and other drugs might improve the survival rate [13], but is not out of the danger of additive toxicity [14].Several genetic alterations have been observed in ovarian cancer, involving deactivation mutations in tumor suppressor genes, such as p53, BRCA1 and BRCA2, and activation mutation and/or amplification of proto-oncogenes, like c-MYC, KRAS and AKT [15]. Recent genomic analysis of The Cancer Genome Atlas reported mutations in p53 gene in 96% of 316 cases of high-grade ovarian serous carcinoma (HGOSC) [16]. Other important genetic changes affect phosphatidyinositol-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) cascade. The mTOR plays a central role in energy metabolism, cell growth/division through macromolecular synthesis and is found to be activated in ovarian cancer [6], which indicates a close relationship between genetic alteration and energy metabolism. It was observed that hexokinase (HK) II, the rate limiting initial enzyme in glycolysis, is overexpressed in ovarian cancer [12]. The genetic alterations and subsequent metabolic remodeling have been found to be associated with the chemoresistance [17], such as association of rictor (mTORC2 component) with resistance to cisplatin [2]. Cisplatin-induced caspase activation causing PTEN cleavage has also been reported as a potential mechanism of chemoresistance in ovarian cancer [18].Mitochondria is a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution [19]. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS) [20]. Beyond the conventional function they have crucial role in certain neurodegenerative diseases and cancer [21][22][23]. Cellular proliferation largely depends on mitochondrial amount, governed by the process of MtBIO [20]. MtBIO is the production of daughter mitochondria usually from previously existed one through a division process of called fission, subsequent growth, and maintenance by fusion and autophagy of mitochondria (mitophagy) [24]. Currently it has been observed that MtBIO is associated with cancer chemoresistance [25,26] through the modulation of associated proteins such as methylation-controlled J-protein (MCJ, also known as DNAJC15) [25,27], prohibitin 1 (PHB-1) [28][29][30], myeloid cell leukemia sequence 1 (MCL-1) [31,32] etc. in ovarian cancer. Thus it can be s...

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“…Srebp1 [17] Lpin [15] Me1, 2 [29] Gamt [14] Crot [16] Cpt1a [16] Cpt1c [16] Npc1/1 [16] Pltp [16] Cel [16] Abca12 [16] Acer2 [16] Apobec1 [16] Dhrs3 [16] Glutaminolyse Gls2 [19,20] Glycolyse Glut1, 4 [7] Tigar [9] Hk2 [13] OxPhos et biogenèse des mitochondries Pgc1a [35] Sco2 [10] Tableau I. Gènes du métabolisme réprimés ou induits par p53. SYNTHÈSE REVUES source de production d'énergie par la mitochondrie (-oxydation des acides gras) dans des situations de carence en glucose ou au cours d'une période de jeûne, notamment en régulant la transcription de Gamt (guanidinoacetate N-methyltransferase) [14], de Lpin (lipo-protein ice nucleator) [15] et de plusieurs carnitine acyl transferases (Crot, Cpt1A et Cpt1C qui conjuguent des groupements carnitine aux acides gras, une étape limitante de leur transport dans la mitochondrie) [16].…”

Section: Statut Redoxunclassified

“…SYNTHÈSE REVUES source de production d'énergie par la mitochondrie (-oxydation des acides gras) dans des situations de carence en glucose ou au cours d'une période de jeûne, notamment en régulant la transcription de Gamt (guanidinoacetate N-methyltransferase) [14], de Lpin (lipo-protein ice nucleator) [15] et de plusieurs carnitine acyl transferases (Crot, Cpt1A et Cpt1C qui conjuguent des groupements carnitine aux acides gras, une étape limitante de leur transport dans la mitochondrie) [16]. p53 a également des effets sur la biosynthèse des lipides en régulant négativement SREBP1 (sterol regulatory element-binding protein 1), un facteur de transcription agissant sur plusieurs gènes essentiels à la biosynthèse des lipides comme Fasn (fatty acid synthase) ou Acly (ATP-citrate lyase) [17].…”

Section: Statut Redoxunclassified

“…Les effets métaboliques de p53 pourraient avoir des rôles importants dans la survenue de certaines pathologies associées au vieillissement. Ainsi, via le contrôle de l'expression de certaines lipoprotéines synthétisées par le foie, il est possible que p53 constitue une ligne de défense contre l'athérosclérose [16]. Cependant, certains des effets provieillissement de p53 ont récemment été couplés à des effets métaboliques faisant intervenir le corégulateur transcriptionnel PGC1 [35], soulignant une fois de plus la complexité des effets métaboliques associés à p53.…”

Section: Quelles Sont Les Fonctions In Vivo Des Réponses Métaboliquesunclassified

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