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https://www.readbyqxmd.com/read/29157081/regulation-of-becn1-mediated-autophagy-by-hspb6-insights-from-a-human-hspb6-s10f-mutant
#1
Guan-Sheng Liu, Hongyan Zhu, Wen-Feng Cai, Xiaohong Wang, Min Jiang, Kobina Essandoh, Elizabeth Vafiadaki, Kobra Haghighi, Chi Keung Lam, George Gardner, George Adly, Persoulla Nicolaou, Despina Sanoudou, Qiangrong Liang, Jack Rubinstein, Guo-Chang Fan, Evangelia G Kranias
HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified a human mutant of HSPB6 (HSPB6(S10F)) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression of this mutant in mouse hearts resulted in remodeling and dysfunction, which progressed to heart failure and early death. These detrimental effects were associated with reduced interaction of mutant HSPB6(S10F) with BECN1/Beclin 1, leading to BECN1 ubiquitination and its proteosomal degradation...
November 20, 2017: Autophagy
https://www.readbyqxmd.com/read/29147952/gemigliptin-a-novel-dipeptidyl-peptidase-iv-inhibitor-exerts-a-synergistic-cytotoxicity-with-the-histone-deacetylase-inhibitor-pxd101-in-thyroid-carcinoma-cells
#2
S H Kim, J G Kang, C S Kim, S-H Ihm, M G Choi, H J Yoo, S J Lee
PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the histone deacetylase inhibitor PXD101 on survival of thyroid carcinoma cells was investigated. METHODS: SW1736, TPC-1, 8505C and BCPAP human thyroid carcinoma cells were used. To assess cell survival, cell viability, the percentage of viable cells and dead cells, cytotoxic activity, ATP levels and FACS analysis were measured. To validate the impact of gemigliptin combined with PXD101, the interactions were estimated by obtaining combination index in cells treated with two agents...
November 16, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29146569/found-in-translation-how-preclinical-research-is-guiding-the-clinical-development-of-the-bcl2-selective-inhibitor-venetoclax
#3
REVIEW
Joel D Leverson, Deepak Sampath, Andrew J Souers, Saul H Rosenberg, Wayne J Fairbrother, Martine Amiot, Marina Konopleva, Anthony Letai
Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax...
November 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29142990/the-chemical-chaperone-pba-reduces-er-stress-and-autophagy-and-increases-collagen-iv-%C3%AE-5-expression-in-cultured-fibroblasts-from-men-with-x-linked-alport-syndrome-and-missense-mutations
#4
Dongmao Wang, Mardhiah Mohammad, Yanyan Wang, Rachel Tan, Lydia S Murray, Sharon Ricardo, Hayat Dagher, Tom van Agtmael, Judy Savige
Introduction: X-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects of chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with missense mutations. Methods: Dermal fibroblast cultures were established from 2 affected men and 3 normals. Proliferation rates were examined, the collagen IV α5 chain localized with immunostaining, and levels of the intra- and extracellular chains quantitated with an in-house enzyme-linked immunosorbent assay...
July 2017: KI Reports
https://www.readbyqxmd.com/read/29141222/jnk-promotes-epithelial-cell-anoikis-by-transcriptional-and-post-translational-regulation-of-bh3-only-proteins
#5
Nomeda Girnius, Roger J Davis
Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29118912/high-expression-of-fibronectin-1-suppresses-apoptosis-through-the-nf-%C3%AE%C2%BAb-pathway-and-is-associated-with-migration-in-nasopharyngeal-carcinoma
#6
Jinting Wang, Lian Deng, Junpeng Huang, Rui Cai, Xiongjie Zhu, Faquan Liu, Qien Wang, Jiren Zhang, Yanfang Zheng
Fibronectin 1 (FN1) is a member of the glycoprotein family located on chromosome 2q35. It has been reported that FN1 is upregulated in many tumors, and its expression is negatively related to the prognosis and survival of cancer patients. Through data analysis, we found that FN1 is upregulated in nasopharyngeal carcinoma (NPC). This study aimed to investigate how FN1 expression affects NPC cell behavior. In this study, we downregulated FN1 in two NPC cell lines, 5-8F (EBV-) and C666-1 (EBV+), and evaluated invasion, migration and apoptosis...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/29099481/viewing-bcl2-and-cell-death-control-from-an-evolutionary-perspective
#7
REVIEW
Andreas Strasser, David L Vaux
The last 30 years of studying BCL2 have brought cell death research into the molecular era, and revealed its relevance to human pathophysiology. Most, if not all metazoans use an evolutionarily conserved process for cellular self destruction that is controlled and implemented by proteins related to BCL2. We propose the anti-apoptotic BCL2-like and pro-apoptotic BH3-only members of the family arose through duplication and modification of genes for the pro-apoptotic multi-BH domain family members, such as BAX and BAK1...
November 3, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29072681/demethylzeylasteral-inhibits-cell-proliferation-and-induces-apoptosis-through-suppressing-mcl1-in-melanoma-cells
#8
Yuzu Zhao, Jiang He, Jun Li, Xingzhi Peng, Xianxing Wang, Zhen Dong, Erhu Zhao, Yaling Liu, Zonghui Wu, Hongjuan Cui
Demethylzeylasteral is one of the extracts of Tripterygium wilfordii Hook F, which plays important roles in multiple biological processes such as inflammation inhibition, as well as immunosuppression. However, anti-cancer function and the underlying mechanisms of demethylzeylasteral in melanoma cells remain unclear. In this study, we demonstrate that demethylzeylasteral has an anti-tumor property in melanoma cells. Demethylzeylasteral not only inhibits cell proliferation through cell cycle arrest at S phase, but also induces cell apoptosis in melanoma cells...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29066822/dysregulated-gene-expressions-of-mex3d-fos-and-bcl2-in-human-induced-neuronal-in-cells-from-nf1-patients-a-pilot-study
#9
Noriaki Sagata, Takahiro A Kato, Shin-Ichi Kano, Masahiro Ohgidani, Norihiro Shimokawa, Mina Sato-Kasai, Kohei Hayakawa, Nobuki Kuwano, Ashley M Wilson, Koko Ishizuka, Shiori Kato, Takeshi Nakahara, Makiko Nakahara-Kido, Daiki Setoyama, Yasunari Sakai, Shouichi Ohga, Masutaka Furue, Akira Sawa, Shigenobu Kanba
Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated)...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29063678/molecular-profiling-and-combinatorial-activity-of-cct068127-a-potent-cdk2-and-cdk9-inhibitor
#10
Steven R Whittaker, Clare Barlow, Mathew P Martin, Caterina Mancusi, Steve Wagner, Annette Self, Elaine Barrie, Robert Te Poele, Swee Sharp, Nathan Brown, Stuart Wilson, Wayne Jackson, Peter M Fischer, Paul A Clarke, Michael I Walton, Edward McDonald, Julian Blagg, Martin Noble, Michelle D Garrett, Paul Workman
Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29053140/measurement-of-bh3-only-protein-tolerance
#11
Haiming Dai, Husheng Ding, Kevin L Peterson, X Wei Meng, Paula A Schneider, Katherine L B Knorr, Scott H Kaufmann
The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15- to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis...
October 20, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29045843/high-throughput-functional-genetic-and-compound-screens-identify-targets-for-senescence-induction-in-cancer
#12
Liqin Wang, Rodrigo Leite de Oliveira, Cun Wang, João M Fernandes Neto, Sara Mainardi, Bastiaan Evers, Cor Lieftink, Ben Morris, Fleur Jochems, Lisa Willemsen, Roderick L Beijersbergen, René Bernards
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29042969/silencing-of-tctn1-inhibits-proliferation-induces-cell-cycle-arrest-and-apoptosis-in-human-thyroid-cancer
#13
Peipei Xu, Xiaotian Xia, Zhili Yang, Yuan Tian, Jianzhong Di, Minggao Guo
Tectonic family member 1 (TCTN1) is one of the tectonic family members, and a regulator of the hedgehog signaling pathway, which has been studied in various cancer types, including prostate and pancreatic cancer. However, its function in thyroid cancer has not been well documented. Therefore, the present study investigated the function of TCTN1 in thyroid cancer using a loss-of-function assay. Lentivirus-mediated RNA interference was applied to downregulate TCTN1 in the thyroid cancer cell lines, CAL62 and 8305C...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29042283/the-pr-1-domain-accounts-for-the-anti-angiogenic-activity-of-a-cysteine-rich-secretory-protein-member-from-the-buccal-glands-of-lampetra-japonica
#14
Dandan Duan, Hongyan Wang, Rong Zhou, Qi Jiang, Rong Xiao
Previous studies have shown that cysteine-rich buccal gland protein (CRBGP) from buccal glands of Lampetra japonica could suppress angiogenesis in chick chorioallantoic membrane models. As CRBGP is composed of a pathogenesis-related group 1 (PR-1) domain and a cysteine-rich domain (CRD), which domain accounts for the effects of CRBGP on anti-angiogenesis? In the present study, recombinant PR-1 and CRD (rL-PR-1 and rL-CRD) were obtained. MTT assays showed rL-PR-1 inhibited the proliferation of HUVECs significantly in a dose-dependent manner with an IC50 of 2μM, while rL-CRD had no obviously inhibitory effect on the proliferation of HUVECs, suggested that PR-1 is the main function domain on the anti-angiogenic activity of CRBGP...
October 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29024661/paclitaxel-reduces-axonal-bclw-to-initiate-ip3r1-dependent-axon-degeneration
#15
Sarah E Pease-Raissi, Maria F Pazyra-Murphy, Yihang Li, Franziska Wachter, Yusuke Fukuda, Sara J Fenstermacher, Lauren A Barclay, Gregory H Bird, Loren D Walensky, Rosalind A Segal
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases...
October 11, 2017: Neuron
https://www.readbyqxmd.com/read/29018077/efficacy-of-venetoclax-as-targeted-therapy-for-relapsed-refractory-t-11-14-multiple-myeloma
#16
Shaji Kumar, Jonathan L Kaufman, Cristina Gasparetto, Joseph Mikhael, Ravi Vij, Brigitte Pegourie, Lofti Benboubker, Thierry Facon, Martine Amiot, Philippe Moreau, Elizabeth A Punnoose, Stefanie Alzate, Martin Dunbar, Tu Xu, Suresh K Agarwal, Sari Heitner Enschede, Joel D Leverson, Jeremy A Ross, Paulo C Maciag, Maria Verdugo, Cyrille Touzeau
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in MM cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase I study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added upon progression during treatment...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/29017053/apoptosis-up-the-ante
#17
Palaniraja Thandapani, Iannis Aifantis
The clinical success of the BH3-mimetic venetoclax has generated increasing interest to target BCL2 family proteins in oncology. In this issue of Cancer Cell, Reyna and colleagues demonstrate the potential of a pharmacological activator of the pro-apoptotic protein BAX to suppress acute myeloid leukemia both alone and together with venetoclax.
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28990517/anesthetic-agents-and-neuronal-autophagy-what-we-know-and-what-we-don-t
#18
Lili Xu, Jianjun Shen, Patrick M McQuillan, Zhiyong Hu
Numerous experimental data have demonstrated that neonatal animal exposure to commonly used anesthetic agents may cause neuronal death resulting in cognitive impairment. The underlying mechanism(s) remain elusive. Depending on the circumstances, autophagy may produce an effect that can be either protective or deleterious. Recent evidence demonstrates that this process can reduce the development of ethanol induced neurotoxicity and, as we know, ethanol has γ-Aminobutyric acid (GABA) agonist and N-methyl-D-aspartate (NMDA) antagonist characteristics similar to commonly used volatile anesthetic agents...
October 9, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28982310/the-dipeptidyl-peptidase-iv-inhibitor-gemigliptin-alone-or-in-combination-with-nvp-auy922-has-a-cytotoxic-activity-in-thyroid-carcinoma-cells
#19
Si Hyoung Kim, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Seong Jin Lee
The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28981117/trehalose-ameliorates-oxidative-stress-mediated-mitochondrial-dysfunction-and-er-stress-via-selective-autophagy-stimulation-and-autophagic-flux-restoration-in-osteoarthritis-development
#20
Qian Tang, Gang Zheng, Zhenhua Feng, Yu Chen, Yiting Lou, Chenggui Wang, Xiaolei Zhang, Yu Zhang, Huazi Xu, Ping Shang, Haixiao Liu
Oxidative stress-related apoptosis and autophagy play crucial roles in the development of osteoarthritis (OA), a progressive cartilage degenerative disease with multifactorial etiologies. Here, we determined autophagic flux changes and apoptosis in human OA and tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. In addition, we explored the potential protective effects of trehalose, a novel Mammalian Target of Rapamycin (mTOR)-independent autophagic inducer, in TBHP-treated mouse chondrocytes and a destabilized medial meniscus (DMM) mouse OA model...
October 5, 2017: Cell Death & Disease
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