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Senescence, cancer, autophagy

Yoo Hong Min, Wootae Kim, Ja-Eun Kim
Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis...
October 4, 2016: Oncotarget
Edward A Ratovitski
Dehydroleucodine (DhL), a natural sesquiterpene lactone from Artemisia douglassiana Besser (Argentine) and Gynoxys verrucosa (Ecuador) was shown to induce a cell death in cancer cells through senescence, apoptosis, and DNA damage. Here, we found that the DhL exposure upregulated the total and phosphorylated (p-Y99) levels of TP73 in human glioblastoma U87-MG cells. We further found that TP73 silencing led to a partial rescue of U87-MG cells from the cell death induced by DhL. Upon the DhL exposure numerous gene targets were upregulated and downregulated through a TP73-dependent transcriptional mechanism...
September 23, 2016: Anti-cancer Agents in Medicinal Chemistry
Andrew Oliveira Silva, Eloisa Dalsin, Giovana Ravizzoni Onzi, Eduardo Cremonese Filippi-Chiela, Guido Lenz
Chemotherapy acts on cancer cells by producing multiple effects on a cell population including cell cycle arrest, necrosis, apoptosis and senescence. However, often a subpopulation of cells survives and the behavior of this subpopulation, which is responsible for cancer recurrence, remains obscure. Here we investigated the in vitro short- and long-term responses of six glioblastoma cell lines to clinically relevant doses of temozolomide for 5 days followed by 23 days of recovery, mimicking the standard schedule used in glioblastoma patient for this drug...
September 23, 2016: Experimental Cell Research
Michal Wozniak, Aleksandra Mielczarek, Malgorzata Czyz
MicroRNAs (miRNAs), which are small non-coding RNA molecules that post-transcriptionally regulate the expression of target genes, control the vast majority of cellular events, including proliferation, differentiation, survival, senescence, autophagy, metabolism and genome stability. Even slight alterations in miRNA expression levels may induce the development of pathological states, including cancer. Several studies have already demonstrated the importance of miRNAs in the regulation of melanocytes. Upregulation of oncogenic miRNAs (oncomiRs), mainly by amplification and translocation of miRNA genes, and downregulation of oncosuppressor miRNAs (anti-oncomiRs) by deletion and other mutations, promoter methylation and abnormal processing contributes to melanoma initiation and progression...
August 31, 2016: Current Medicinal Chemistry
Elisa Feller Gonçalves da Silva, Gabriele Catyana Krause, Kelly Goulart Lima, Gabriela Viegas Haute, Leonardo Pedrazza, Fernanda Cristina Mesquita, Bruno Souza Basso, Anderson Catarina Velasquez, Fernanda Bordignon Nunes, Jarbas Rodrigues de Oliveira
Hepatocellular carcinoma is the most prevalent type of tumor among primary tumors affecting the liver. Rapamycin is currently used as a basis for chemotherapy in the treatment of cancers, including the liver. Because it shows several adverse effects, minimizing these effects without compromising efficacy is important. In this sense other drugs may be used concomitantly. One of these drugs is fructose-1,6-bisphosphate (FBP), which has shown therapeutic effect in various pathological situations, having antioxidant and anti-inflammatory proprieties...
September 20, 2016: Oncology Reports
Ravi Amaravadi, Alec C Kimmelman, Eileen White
Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumor-promoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified...
September 1, 2016: Genes & Development
Ruoyu Miao, Yan Wu, Haohai Zhang, Huandi Zhou, Xiaofeng Sun, Eva Csizmadia, Lian He, Yi Zhao, Chengyu Jiang, Rebecca A Miksad, Tahereh Ghaziani, Simon C Robson, Haitao Zhao
Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo...
2016: Scientific Reports
Yang Sun, Long Jin, Jia-Hua Liu, Yu-Xia Sui, Li-Li Han, Xiao-Li Shen
We aimed to determine the effects of the inhibition of enhancer of zeste homolog 2 (EZH2) gene expression on the cisplatin resistance of the human ovarian cancer cell line, SKOV3/DDP, and to identify the underlying mechanisms. SKOV3/DDP cells were stably transfected with pSUPER-EZH2 (EZH2 RNA interference plasmid) or pcDNA3.1-EZH2 (EZH2 gene overexpression plasmid) using the lipofection method. Real-time fluorescence quantitative reverse transcription polymerase chain reaction and western blotting confirmed that EZH2 expression was downregulated in pSUPER-EZH2-transfected cells...
September 2016: Cancer Biotherapy & Radiopharmaceuticals
Hanna Dellago, Madhusudhan Reddy Bobbili, Johannes Grillari
The miR-17-92 cluster, led by its most prominent member, miR-17-5p, has been identified as the first miRNA with oncogenic potential. Thus, the whole cluster containing miR-17-5p has been termed oncomiR-1. It is strongly expressed in embryonic stem cells and has essential roles in vital processes like cell cycle regulation, proliferation and apoptosis. The importance of miR-17-5p for fundamental biological processes is underscored by the fact that a miR17-deficient mouse is neonatally lethal. Recently, miR-17-5p was identified in the context of aging, since it is comprised in a common signature of miRNAs that is downregulated in several models of aging research...
August 31, 2016: Gerontology
Véronique Bourdeau, Gerardo Ferbeyre
Senescence is a natural anticancer defense program disabled in tumor cells. We discovered that deregulated CDK4 (cyclin dependant kinase 4) and CDK6 activities contribute to senescence bypass during tumorigenesis and that their inhibition restores the senescence response in tumor cells. CDK4 and CDK6 phosphorylate RB1/RB, preventing its inhibitory interaction with the E2Fs, the cell cycle transcription factors. However, we also found that CDK4 interacts and phosphorylates the DNMT1 (DNA methyltransferase 1) protein protecting it from macroautophagy/autophagy-mediated protein degradation...
October 2, 2016: Autophagy
Francesca De Amicis, Carmela Guido, Marta Santoro, Francesca Giordano, Ada Donà, Pietro Rizza, Michele Pellegrino, Ida Perrotta, Daniela Bonofiglio, Diego Sisci, Maria Luisa Panno, Donatella Tramontano, Saveria Aquila, Sebastiano Andò
Loss of progesterone-receptors (PR) expression is associated with breast cancer progression. Herein we provide evidence that OHPg/PR-B through Beclin-1 evoke autophagy-senescence transition, in breast cancer cells. Specifically, OHPg increases Beclin-1 expression through a transcriptional mechanism due to the occupancy of Beclin-1 promoter by PR-B, together with the transcriptional coactivator SRC-2. This complex binds at a canonical half progesterone responsive element, which is fundamental for OHPg effects, as shown by site-directed mutagenesis...
July 23, 2016: Oncotarget
Shuang Zhao, Shu-Rui Chen, Xue-Feng Yang, Dao-Fu Shen, Yasuo Takano, Rong-Jian Su, Hua-Chuan Zheng
Here, BTG1 overexpression inhibited proliferation, induced differentiation, autophagy, and apoptosis in colorectal cancer cells (p<0.05). BTG1 overexpression reduced mitochondrial membrane potential and caused senescence in HCT-116 transfectants (p<0.05). BTG1-induced G2 arrest might be related to Cyclin B1 and Cdc25B hypoexpression in HCT-15 transfectants, while G1 arrest in HCT-116 transfectants overexpressing p21 and p27. BTG1 overexpression decreased the expression of Bcl-2, Bcl-xL, XIAP, Akt1 or survivin and increased the expression of Bax or p53 in colorectal cancer cells...
July 18, 2016: Oncotarget
Koji Taniguchi, Shinichiro Yamachika, Feng He, Michael Karin
p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies...
August 2016: FEBS Letters
Hanlin Zhang, Daniel J Puleston, Anna Katharina Simon
With extension of the average lifespan, aging has become a heavy burden in society. Immune senescence is a key risk factor for many age-related diseases such as cancer and increased infections in the elderly, and hence has elicited much attention in recent years. As our body's guardian, the immune system maintains systemic health through removal of pathogens and damage. Autophagy is an important cellular 'clearance' process by which a cell internally delivers damaged organelles and macromolecules to lysosomes for degradation...
August 2016: Trends in Molecular Medicine
Hong-Rong Fei, Hua- Tian, Xiao-Lei Zhou, Ming-Feng Yang, Bao-Liang Sun, Xiao-Yi Yang, Peng- Jiao, Feng-Ze Wang
Autophagy modulation has been considered as a potential therapeutic strategy for lung diseases. The PI3K-Akt-mTOR pathway may be one of the main targets for regulation of autophagy. We previously reported that a PI3K/mTOR dual inhibitor PF-04691502 suppressed hepatoma cells growth in vitro. However, it is still unclear whether PF-04691502 induces autophagy and its roles in DNA damage and cell death in human lung cancer cells. In this study, we investigate the effects of PF-04691502 on the autophagy and its correlation with cell apoptosis and DNA damage in non-small-cell lung cancer (NSCLC) cell lines...
September 2016: International Journal of Biochemistry & Cell Biology
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
The AMP-activated protein kinase (AMPK) and hypoxia-inducible factor (HIF) signaling pathways are evolutionarily-conserved survival mechanisms responding to two fundamental stresses, energy deficiency and/or oxygen deprivation. The AMPK and HIF pathways regulate the function of a survival network with several transcription factors, e.g. FOXO, NF-κB, NRF2, and p53, as well as with protein kinases and other factors, such as mTOR, ULK1, HDAC5, and SIRT1. Given that AMPK and HIF activation can enhance not only healthspan and lifespan but also cancer growth in a context-dependent manner; it seems that cancer cells can hijack certain survival factors to maintain their growth in harsh conditions...
August 2016: Biogerontology
Nicolas Malaquin, Aurélie Martinez, Francis Rodier
Cellular senescence is historically associated with cancer suppression and aging. Recently, the reach of the senescence genetic program has been extended to include the ability of senescent cells to actively participate in tissue remodelling during many physiological processes, including placental biology, embryonic patterning, wound healing, and tissue stress responses caused by cancer therapy. Besides growth arrest, a significant feature of senescent cells is their ability to modify their immediate microenvironment using a senescence-associated (SA) secretome, commonly termed the SA secretory phenotype (SASP)...
September 2016: Experimental Gerontology
Yuji Nakayama, Toshiaki Inoue
Microtubule poisons inhibit spindle function, leading to activation of spindle assembly checkpoint (SAC) and mitotic arrest. Cell death occurring in prolonged mitosis is the first target of microtubule poisons in cancer therapies. However, even in the presence of microtubule poisons, SAC and mitotic arrest are not permanent, and the surviving cells exit the mitosis without cytokinesis (mitotic slippage), becoming tetraploid. Another target of microtubule poisons-based cancer therapy is antiproliferative fate after mitotic slippage...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mariana Acevedo, Mathieu Vernier, Lian Mignacca, Frédéric Lessard, Geneviève Huot, Olga Moiseeva, Véronique Bourdeau, Gerardo Ferbeyre
Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models...
June 1, 2016: Cancer Research
Jia-An Zhang, Bing-Rong Zhou, Yang Xu, Xu Chen, Juan Liu, Maya Gozali, Di Wu, Zhi-Qiang Yin, Dan Luo
Autophagy is a cellular catabolic mechanism that is activated in response to stress conditions, including ultraviolet (UV) irradiation, starvation, and misfolded protein accumulation. Abnormalities in autophagy are associated with several pathologies, including aging and cancer. Furthermore, recent studies have demonstrated that microRNAs (miRNAs) are potent modulators of the autophagy pathway. As a result, the current study aims to elucidate the role of the autophagy-related miRNA miR-23ain the process of photoaging...
May 13, 2016: Oncotarget
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