AMPK Promotes p53 Acetylation via Phosphorylation and Inactivation of SIRT1 in Liver Cancer Cells

Lee, Chi Wai; Wong, Leo Lap-Yan; Tse, Edith Yuk-Ting; Liu, Heong Fai; Leong, Veronica Yee-Law; Lee, Joyce Man‐Fong; Hardie, D. Grahame; Ng, Irene Oi–Lin; Ching, Yick–Pang

doi:10.1158/0008-5472.can-12-0429

Cited by 192 publications

(186 citation statements)

References 32 publications

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“…In addition, the deacetylase activity of Sirt1 was observed to decrease when Sirt1 mutants were transcribed and translated using the site-directed mutagenesis method in a model of carcinogenesis, which increased the sensitivity of cells to DNA damage and the oxidative stress response (26). Further studies demonstrated that the addition of a specific inhibitor of Sirt1, 5' adenosine monophosphate-activated protein kinase, into human hepatoma HepG2 and PLC/PRF/5 cells led to significant reductions in the activity and function of Sirt1, resulting in increased acetylation and transcriptional activity of the p53 protein (27,28). In addition, previous studies noted that Sirt1 expression in primary colorectal carcinoma was significantly increased, suggesting that Sirt1 is key in the occurrence and development of intestinal tumors (29).…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of Sirt1 in colorectal cancer

Jiang

Pan

et al. 2015

Oncology Letters

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Abstract. The objective of the present study was to examine the expression of Silent information regulator 1 (Sirt1) in colorectal cancer and peritumoral normal mucosa tissue, and therefore analyze the role and molecular mechanism of Sirt1 in the pathogenesis of colorectal cancer. Colorectal cancer tissue specimens were employed as the experimental group, and adjacent normal mucosa tissues >5 cm from tumor lesions were used as the control group. The expression of Sirt1 was detected by the immunohistochemical streptavidin peroxidase detection method in paraffin-embedded sections, whilst Sirt1 protein expression was examined by western blot analysis in the fresh tissues. Sirt1 protein was primarily expressed in the nuclei of the tumor cells, and positive staining was brownish-yellow in color. The relative expression quantities of Sirt1 in the peritumoral normal rectal mucosa and rectal carcinoma were 1.15 and 2.62, and the differences between the two groups were statistically significant (P<0.05). The expression level of Sirt1 in colorectal carcinoma was significantly associated with the depth of tumor invasion, differentiation and tumor size (P<0.05). Sirt1 expression was also found to be associated with tumor tissue type, lymph node metastasis, Duke's stage and patient age. These characteristics combined may therefore be used as markers for the early diagnosis of colorectal cancer pathogenesis. IntroductionColorectal cancer occurs in the colorectal mucosa and colonic glands and is one of the most common types of malignant tumor of the digestive system (1,2). The worldwide incidence and mortality rates of colorectal cancer increased significantly between 2009 and 2013; in 2013, a total of 142,820 new cases were diagnosed and 50,830 mortalities occurred as a result of colorectal cancer (3). Thus, this malignancy presents a serious threat to human health (1,2). Clinical and pathological data of patients with colorectal cancer in China have demonstrated the following pathogenic characteristics: The number of patients in cities is higher than that in the countryside, indicating a clear urbanization trend; and patients <30 years of age account for >10% of the total number of patients, demonstrating a clear trend towards older age (4). Surgical resection is currently the main method used for the treatment of colorectal cancer. However, as significant symptoms are often not present in the early stages of the disease, patients are frequently diagnosed in the later stages; by this time, the optimal period for surgery has passed. Furthermore, metastasis or recurrence occurs in a large number of patients following surgical resection, affecting the prognosis of the patients. Therefore, the five-year survival rate is low (64%), posing a serious threat to patient health (5,6).The occurrence and pathogenesis of colorectal cancer is a complex, multistep process, regulated by a number of different genes (1). A total of 25% of patients with colorectal cancer have a genetic history, which is associated with familial adenomatous pol...

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Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of Sirt1 in colorectal cancer

Jiang

Pan

et al. 2015

Oncology Letters

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“…AMPK is known to function as an intracellular energy sensor, being activated in response to an increased AMP⁄ATP ratio, a condition of energetic stress, to promote the catabolic pathway, thereby inhibiting cell proliferation (18,19). Growing evidence suggests that AMPK is dysregulated in most cancer tissues, including HCC, when compared to normal tissues (26)(27)(28), and several studies have shown that AMPK activators exhibit inhibitory effects on HCC growth (21,26,27,(29)(30)(31)36). Scientific interest continues to grow in the search for molecular pathways and novel compounds that target AMPK signaling as new potential therapeutic options for HCC.…”

Section: Discussionmentioning

confidence: 99%

“…Under metabolic stress conditions, where decreases in intracellular ATP and increases in AMP levels are common, AMPK is activated by phosphorylation of a critical amino acid residue (Thr172) to function as a major metabolic switch that maintains energy homeostasis (18,19). Once activated, AMPK suppresses cell proliferation in tumor as well as non-tumor cells, through regulation of the cell cycle, apoptosis, autophagy, and inhibition of protein synthesis (20)(21)(22)(23)(24)(25). Current evidence supports the alteration of AMPK levels in various cancers, implicating AMPK as a potential target for prevention and/or treatment of cancer, specifically HCC (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

Park

Jeong

Jeong³

et al. 2015

International Journal of Oncology

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Abstract. The Kalopanax septemlobus leaf (Thunb.) Koidz. has been used as a traditional medicine herb for the treatment of various human diseases for hundreds of years. In this study, we investigated the mechanism underlying the inhibitory effects of an ethanol extract of K. septemlobus leaf (EEKS) on proliferation of HepG2 hepatocellular carcinoma cells. For this study, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, DAPI (4,6-diamidino-2-phenylindole) staining, agarose gel electrophoresis, and flow cytometry. Measurements of the mitochondrial membrane potential (MMP), caspase activity assays and western blots were conducted to determine whether HepG2 cell death occurred by apoptosis. Treatment of HepG2 cells with EEKS concentration-dependently reduced cell survival while significantly increasing the ratio of apoptotic cells. EEKS treatment increased the levels of the death receptors (DRs), DR4 and DR5, and activated caspases, as well as promoting proteolytic degradation of poly(ADP-ribose)-polymerase associated with the downregulation of protein expression of members of the inhibitor of apoptosis protein family. Treatment with EEKS also caused truncation of Bid, translocation of pro-apoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. However, treatment of HepG2 cells with a pan-caspase inhibitor reversed EEKS-induced apoptosis and growth suppression, indicating that EEKS appears to induce apoptosis though a caspase-dependent mechanism involving both intrinsic and extrinsic apoptotic pathways. In addition, the phosphorylation level of AMP-activated protein kinase (AMPK) was elevated when cells were exposed to EEKS. A specific inhibitor for AMPK attenuated the EEKS-induced activation of caspases, and consequently prevented the EEKS-induced apoptosis and reduction in cell viability. Overall, our findings suggest that EEKS inhibits the growth of HepG2 cells by inducing AMPK-mediated caspase-dependent apoptosis, suggesting the potential therapeutic application of EEKS in the treatment or prevention of cancers.

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“…This involves the inhibition of energy‐consuming processes such as fatty acid and protein biosynthesis, while increasing catabolism by promoting autophagy and fatty acid oxidation (Carling et al ., 2012; Faubert et al ., 2015; Mihaylova and Shaw, 2011). In addition to direct regulation of key metabolic checkpoints, AMPK may also inhibit tumorigenesis through upregulation of transcription factors such as the tumor suppressor p53, which is mutated in approximately 80% of all cancers (He et al ., 2014; Jones et al ., 2005; Lee et al ., 2012). Mutation or genetic deficiency of p53 may also act to suppress AMPK activity (Zhou et al ., 2014), suggesting that the activities of p53 and AMPK may be intimately linked to match energy availability with cell proliferation (Adamovich et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

AMPK β1 reduces tumor progression and improves survival in p53 null mice

Houde

Donzelli²,

Sacconi³

et al. 2017

Molecular Oncology

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The AMP‐activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK β1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK β1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK β1 accelerates the appearance of a T‐cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin‐1β (IL1β), reductions in acetyl‐CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK β1 subunit accelerate the development of T‐cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53‐mutant tumors.

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AMPK Promotes p53 Acetylation via Phosphorylation and Inactivation of SIRT1 in Liver Cancer Cells

Cited by 192 publications

References 32 publications

Expression and clinical significance of Sirt1 in colorectal cancer

Expression and clinical significance of Sirt1 in colorectal cancer

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

AMPK β1 reduces tumor progression and improves survival in p53 null mice

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