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Open accessJournal ArticleDOI: 10.1038/S41388-021-01707-7

PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer.

02 Mar 2021-Oncogene (Nature Publishing Group)-Vol. 40, Iss: 13, pp 2355-2366
Abstract: Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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7 results found


Open accessJournal ArticleDOI: 10.3390/CANCERS13092153
Hong Sheng Cheng1, Yun Sheng Yip1, Eldeen Kai Yi Lim1, Walter Wahli1  +3 moreInstitutions (3)
29 Apr 2021-Cancers
Abstract: Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

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Topics: Tumor microenvironment (59%), Autocrine signalling (55%), Stromal cell (55%) ... show more

4 Citations


Open accessJournal ArticleDOI: 10.1080/21655979.2021.1960775
Gang Chen1, Mingwei Yu1, Jianqiao Cao1, Huishan Zhao1  +3 moreInstitutions (1)
01 Jan 2021-Bioengineered bugs
Abstract: Breast cancer (BC) is a malignancy with high incidence among women in the world. This study aims to screen key genes and potential prognostic biomarkers for BC using bioinformatics analysis. Total 58 normal tissues and 203 cancer tissues were collected from three Gene Expression Omnibus (GEO) gene expression profiles, and then the differential expressed genes (DEGs) were identified. Subsequently, the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway were analyzed to investigate the biological function of DEGs. Additionally, hub genes were screened by constructing a protein-protein interaction (PPI) network. Then, we explored the prognostic value and molecular mechanism of these hub genes using Kaplan-Meier (KM) curve and Gene Set Enrichment Analysis (GSEA). As a result, 42 up-regulated and 82 down-regulated DEGs were screened out from GEO datasets. The DEGs were mainly related to cell cycles and cell proliferation by GO and KEGG pathway analysis. Furthermore, 12 hub genes (FN1, AURKA, CCNB1, BUB1B, PRC1, TPX2, NUSAP1, TOP2A, KIF20A, KIF2C, RRM2, ASPM) with a high degree were identified initially, among which, 11 hub genes were significantly correlated with the prognosis of BC patients based on the Kaplan-Meier-plotter. GSEA reviewed that these hub genes correlated with KEGG_CELL_CYCLE and HALLMARK_P53_PATHWAY. In conclusion, this study identified 11 key genes as BC potential prognosis biomarkers on the basis of integrated bioinformatics analysis. This finding will improve our knowledge of the BC progress and mechanisms.

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Topics: KEGG (56%)

3 Citations


Open accessJournal ArticleDOI: 10.3390/CANCERS13143445
09 Jul 2021-Cancers
Abstract: Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBα), Akt2(PKBβ) and Akt3(PKBγ). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.

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Topics: PI3K/AKT/mTOR pathway (65%), Protein kinase B (64%), AKT1 (61%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.1186/S13045-021-01137-8
Hui Hua1, Hongying Zhang1, Jingzhu Chen1, Jiao Wang2  +2 moreInstitutions (2)
Abstract: Biomarkers-guided precision therapeutics has revolutionized the clinical development and administration of molecular-targeted anticancer agents. Tailored precision cancer therapy exhibits better response rate compared to unselective treatment. Protein kinases have critical roles in cell signaling, metabolism, proliferation, survival and migration. Aberrant activation of protein kinases is critical for tumor growth and progression. Hence, protein kinases are key targets for molecular targeted cancer therapy. The serine/threonine kinase Akt is frequently activated in various types of cancer. Activation of Akt promotes tumor progression and drug resistance. Since the first Akt inhibitor was reported in 2000, many Akt inhibitors have been developed and evaluated in either early or late stage of clinical trials, which take advantage of liquid biopsy and genomic or molecular profiling to realize personalized cancer therapy. Two inhibitors, capivasertib and ipatasertib, are being tested in phase III clinical trials for cancer therapy. Here, we highlight recent progress of Akt signaling pathway, review the up-to-date data from clinical studies of Akt inhibitors and discuss the potential biomarkers that may help personalized treatment of cancer with Akt inhibitors. In addition, we also discuss how Akt may confer the vulnerability of cancer cells to some kinds of anticancer agents.

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Topics: Protein kinase B (61%), Targeted therapy (61%), Ipatasertib (59%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.3390/ANTIOX10081188
Fabiola Paciello1, Anna Pisani1, Rolando Rolesi1, Vincent Escarrat1  +5 moreInstitutions (1)
26 Jul 2021-Antioxidants
Abstract: The cross-talk between oxidative stress and inflammation seems to play a key role in noise-induced hearing loss. Several studies have addressed the role of PPAR receptors in mediating antioxidant and anti-inflammatory effects and, although its protective activity has been demonstrated in several tissues, less is known about how PPARs could be involved in cochlear dysfunction induced by noise exposure. In this study, we used an in vivo model of noise-induced hearing loss to investigate how oxidative stress and inflammation participate in cochlear dysfunction through PPAR signaling pathways. Specifically, we found a progressive decrease in PPAR expression in the cochlea after acoustic trauma, paralleled by an increase in oxidative stress and inflammation. By comparing an antioxidant (Q-ter) and an anti-inflammatory (Anakinra) treatment, we demonstrated that oxidative stress is the primary element of damage in noise-induced cochlear injury and that increased inflammation can be considered a consequence of PPAR down-regulation induced by ROS production. Indeed, by decreasing oxidative stress, PPARs returned to control values, reactivating the negative control on inflammation in a feedback loop.

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Topics: Oxidative stress (54%), Inflammation (50%)

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40 results found


Open accessJournal ArticleDOI: 10.1186/S13059-014-0550-8
05 Dec 2014-Genome Biology
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .

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Topics: MRNA Sequencing (54%), Integrator complex (51%), Count data (50%) ... show more

29,675 Citations


Open accessJournal ArticleDOI: 10.1038/NMETH.1923
01 Apr 2012-Nature Methods
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

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27,973 Citations


Open accessJournal ArticleDOI: 10.3322/CAAC.21254
Abstract: Each year the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the United States in 2015. During the most recent 5 years for which there are data (2007-2011), delay-adjusted cancer incidence rates (13 oldest SEER registries) declined by 1.8% per year in men and were stable in women, while cancer death rates nationwide decreased by 1.8% per year in men and by 1.4% per year in women. The overall cancer death rate decreased from 215.1 (per 100,000 population) in 1991 to 168.7 in 2011, a total relative decline of 22%. However, the magnitude of the decline varied by state, and was generally lowest in the South (∼15%) and highest in the Northeast (≥20%). For example, there were declines of 25% to 30% in Maryland, New Jersey, Massachusetts, New York, and Delaware, which collectively averted 29,000 cancer deaths in 2011 as a result of this progress. Further gains can be accelerated by applying existing cancer control knowledge across all segments of the population.

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Topics: Cancer Death Rate (64%), Mortality rate (60%), Cancer (54%) ... show more

10,414 Citations


Open accessJournal ArticleDOI: 10.1186/GB-2013-14-4-R36
Daehwan Kim1, Daehwan Kim2, Geo Pertea3, Cole Trapnell4  +5 moreInstitutions (7)
25 Apr 2013-Genome Biology
Abstract: TopHat is a popular spliced aligner for RNA-sequence (RNA-seq) experiments. In this paper, we describe TopHat2, which incorporates many significant enhancements to TopHat. TopHat2 can align reads of various lengths produced by the latest sequencing technologies, while allowing for variable-length indels with respect to the reference genome. In addition to de novo spliced alignment, TopHat2 can align reads across fusion breaks, which can occur after genomic translocations. TopHat2 combines the ability to identify novel splice sites with direct mapping to known transcripts, producing sensitive and accurate alignments, even for highly repetitive genomes or in the presence of pseudogenes. TopHat2 is available at http://ccb.jhu.edu/software/tophat.

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Topics: Reference genome (51%), Pseudogene (50%)

9,972 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2007.06.009
Brendan D. Manning1, Lewis C. Cantley2Institutions (2)
29 Jun 2007-Cell
Abstract: The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.

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Topics: Protein kinase B (69%), AKT1 (67%), PI3K/AKT/mTOR pathway (65%) ... show more

5,088 Citations