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Ubiquitin myeloma

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https://www.readbyqxmd.com/read/29863498/destabilizing-nek2-overcomes-resistance-to-proteasome-inhibition-in-multiple-myeloma
#1
Reinaldo Franqui-Machin, Mu Hao, Hua Bai, Zhimin Gu, Xin Zhan, Hasem Habelhah, Yogesh Jethava, Lugui Qiu, Ivana Frech, Guido Tricot, Fenghuang Zhan
Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization...
June 4, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29807510/the-emerging-roles-of-the-herc-ubiquitin-ligases-in-cancer
#2
Xinliang Mao, Gautam Sethi, Zubin Zhang, Qi Wang
BACKGROUND: The HERC family containing six members from HERC1 to HERC6 that are featured with the HECT domains that exerts ubiquitin ligase activity and the RCC1-like domains that are involved in cell cycle regulation. Although identified as early as 1990s, their biological functions are extensively studied in recent years. More and more researches have demonstrated that the HERC ubiquitin ligases are widely engaged in carcinogenesis, however, there lacks a comprehensive and instructive analysis...
May 27, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29746508/cul5-is-required-for-thalidomide-dependent-inhibition-of-cellular-proliferation
#3
Bryan Kunkler, Daniel Salamango, Zachary J DeBruine, Caitlin Ploch, Shirley Dean, David Grossens, Michael P Hledin, Gabriel A Marquez, Julie Madden, Abigayle Schnell, Michael Short, Maria A Burnatowska-Hledin
Angiogenesis is essential for cancer metastasis, thus the discovery and characterization of molecules that inhibit this process is important. Thalidomide is a teratogenic drug which is known to inhibit angiogenesis and effectively inhibit cancer metastasis, yet the specific cellular targets for its effect are not well known. We discovered that CUL5 (previously identified as VACM-1), a scaffold protein in E3 ligase complexes, is involved in thalidomide-dependent inhibition of endothelial cell growth. Our results show that in human endothelial cells (HUVEC), thalidomide-dependent decrease in cell growth was associated with decreased nuclear localization of CUL5...
2018: PloS One
https://www.readbyqxmd.com/read/29741882/identification-and-structure-activity-relationship-of-hdac6-zinc-finger-ubiquitin-binding-domain-inhibitors
#4
Renato Ferreira de Freitas, Rachel J Harding, Ivan Franzoni, Mani Ravichandran, Mandeep K Mann, Hui Ouyang, Mark Lautens, Vijayaratnam Santhakumar, Cheryl H Arrowsmith, Matthieu Schapira
HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity...
May 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29628465/-pharmacological-characteristics-and-clinical-study-results-of-the-oral-proteasome-inhibitor-ixazomib-ninlaro-%C3%A2-capsules-2-3-mg-3-mg-and-4-mg
#5
Michiko Machida, Shinichi Fukunaga, Takahito Hara
Ixazomib (Ninlaro® capsule) is an oral small molecule 20S proteasome inhibitor created by Millennium Pharmaceuticals, Inc (Takeda Oncology Company). Ubiquitin proteasome system is a major regulatory system for maintaining protein homeostasis, and an important mechanism for degrading proteins, such as those involved in proliferation regulation, cell cycle regulation and apoptosis, in cells. Ixazomib selectively and reversibly binds to the β5 subunit of the 20S proteasome, inhibits its chymotrypsin-like activity, and thereby accumulates ubiquitinated proteins...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#6
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29581234/traf-interacting-protein-with-forkhead-associated-domain-tifa-transduces-dna-damage-induced-activation-of-nf-%C3%AE%C2%BAb
#7
Jingxuan Fu, Daoyuan Huang, Fuwen Yuan, Nan Xie, Qian Li, Xinpei Sun, Xuehong Zhou, Guodong Li, Tanjun Tong, Yu Zhang
DNA damage-induced NF-κB activation and the secretion of inflammatory cytokines play crucial roles in carcinogenesis and cellular senescence. However, the underlying mechanisms, especially the initial sensors and transducers connecting the nuclear DNA damage signal with cytoplasmic NF-κB activation remain incompletely understood. Here, we report that TRAF-interacting protein with forkhead-associated domain (TIFA), an established NF-κB activator in the cytosol, unexpectedly exhibited nuclear translocation and accumulation on damaged chromatin following genotoxic stress...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29548576/design-synthesis-and-biological-evaluation-of-novel-ubiquitin-activating-enzyme-inhibitors
#8
Yukihiro Itoh, Miki Suzuki
Ubiquitin-activating enzyme (E1), which catalyzes the activation of ubiquitin in the initial step of the ubiquitination cascade, is a potential therapeutic target in multiple myeloma and breast cancer treatment. However, only a few E1 inhibitors have been reported to date. Moreover, there has been little medicinal chemistry research on the three-dimensional structure of E1. Therefore, in the present study, we attempted to identify novel E1 inhibitors using structure-based drug design. Following the rational design, synthesis, and in vitro biological evaluation of several such compounds, we identified a reversible E1 inhibitor (4b)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29535191/rapid-induction-of-p62-and-gabarapl1-upon-proteasome-inhibition-promotes-survival-before-autophagy-activation
#9
Zhe Sha, Helena M Schnell, Kerstin Ruoff, Alfred Goldberg
Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62 , which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes...
May 7, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29515784/potent-anti-tumor-activity-of-a-syringolin-analog-in-multiple-myeloma-a-dual-inhibitor-of-proteasome-activity-targeting-%C3%AE-2-and-%C3%AE-5-subunits
#10
Takashi Yoshida, Masaki Ri, Takashi Kanamori, Sho Aoki, Reham Ashour, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Shun Kitahata, Takuya Chiba, Satoshi Ichikawa, Shinsuke Iida
Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29504425/proteasome-20s-in-multiple-myeloma-comparison-of-concentration-and-chymotrypsin-like-activity-in-plasma-and-serum
#11
Wioletta Romaniuk, Joanna Kalita, Halina Ostrowska, Janusz Kloczko
The ubiquitin-proteasome system is relevant in the pathobiology of many haematological malignancies, including multiple myeloma. The assessment of proteasome concentration and chymotrypsin-like (ChT-L) activity might constitute a new approach to diagnosis, prognosis and monitoring of anticancer treatment of patients with haematological malignancies and other diseases. The aim of our study was to determine which material, plasma or serum, is better for measuring chymotrypsin-like (ChT-L) activity and proteasome concentration...
March 5, 2018: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/29497034/proteasome-inhibition-blocks-necroptosis-by-attenuating-death-complex-aggregation
#12
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29467225/the-transmembrane-protein-tmepai-induces-myeloma-cell-apoptosis-by-promoting-degradation-of-the-c-maf-transcription-factor
#13
Yanyun Du, Yan Liu, Yujia Xu, Jiaxiang Juan, Zubin Zhang, Zhuan Xu, Biyin Cao, Qi Wang, Yuanying Zeng, Xinliang Mao
TMEPAI (transmembrane prostate androgen-induced protein, also called prostate transmembrane protein, androgen-induced 1 (PMEPA1)) is a type I transmembrane (TM) protein, but its cellular function is largely unknown. Here, studying factors influencing the stability of c-Maf, a critical transcription factor in multiple myeloma (MM), we found that TMEPAI induced c-Maf degradation. We observed that TMEPAI recruited NEDD4 (neural precursor cell expressed, developmentally down-regulated 4), a WW domain-containing ubiquitin ligase, to c-Maf, leading to its degradation through the proteasomal pathway...
April 20, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29450620/targeting-the-neddylation-pathway-in-cells-as-a-potential-therapeutic-approach-for-diseases
#14
REVIEW
Jie Ying, Miaomiao Zhang, Xiaoyan Qiu, Yu Lu
The ubiquitin-proteasome system (UPS) is an important system that regulates the balance of intracellular proteins, and it is involved in the regulation of multiple vital biological processes. The approval of bortezomib for relapsed and refractory multiple myeloma has proven that agents targeting the UPS have the potential to be effective treatment strategies for diseases. Among of all of the components of the UPS, cullin-RING ligases (CRLs) are the focus of research. CRLs are the largest family of ubiquitin E3 ligases and they play a critical role in substrate binding...
May 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29327347/unique-anti-myeloma-activity-by-thiazolidine-2-4-dione-compounds-with-pim-inhibiting-activity
#15
Shiro Fujii, Shingen Nakamura, Asuka Oda, Hirokazu Miki, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Ariunzaya Bat-Erdene, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Itsuro Endo, Sumiko Yoshida, Ken-Ichi Aihara, Kiyoe Kurahashi, Takeshi Harada, Kumiko Kagawa, Michiyasu Nakao, Shigeki Sano, Masahiro Abe
Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447...
January 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29318562/targeting-deubiquitinases-in-cancer
#16
Joseph S Bednash, Rama K Mallampalli
The ubiquitin-proteasome system (UPS) is a complex and robust metabolic pathway that contributes to the regulation of many key cellular processes including the cell cycle, cell division, and response to external stimuli. Ubiquitin ligases, which tag proteins with ubiquitin, are opposed by deubiquitinase enzymes (DUBs). The relative activity of these enzymes allows for a dynamic balance that determines the abundance and activity of cellular proteins. Targeting the UPS in cancer has proven successful, as evidenced by use of bortezomib, a proteasome inhibitor, in multiple myeloma...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29168472/characterization-of-naturally-occurring-pentacyclic-triterpenes-as-novel-inhibitors-of-deubiquitinating-protease-usp7-with-anticancer-activity-in-vitro
#17
Bo Jing, Meng Liu, Li Yang, Hai-Yan Cai, Jie-Bo Chen, Ze-Xi Li, Xi Kou, Yun-Zhao Wu, Dong-Jun Qin, Li Zhou, Jin Jin, Hu Lei, Han-Zhang Xu, Wei-Wei Wang, Ying-Li Wu
Deubiquitinating protease USP7 is a promising therapeutic target for cancer treatment, and interest in developing USP7 inhibitors has greatly increased. In the present study, we reported a series of natural pentacyclic triterpenes with USP7 inhibitory activity in vitro. Among them, both the ursane triterpenes and oleanane triterpenes were more active than the lupine triterpenes, whereas ursolic acid was the most potent with IC50 of 7.0±1.5 μmol/L. Molecular docking studies showed that ursolic acid might occupy the ubiquitin binding pocket of USP7, with the 17-carboxyl group and 3-hydroxyl group playing a vital role in the USP7-ursolic acid interaction...
March 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29134486/proteasome-associated-deubiquitinases-and-cancer
#18
REVIEW
Arjan Mofers, Paola Pellegrini, Stig Linder, Pádraig D'Arcy
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types...
December 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29107984/treatment-with-proteasome-inhibitor-bortezomib-decreases-organic-anion-transporting-polypeptide-oatp-1b3-mediated-transport-in-a-substrate-dependent-manner
#19
Khondoker Alam, Taleah Farasyn, Alexandra Crowe, Kai Ding, Wei Yue
OATP1B1 and OATP1B3 mediate hepatic uptake of many drugs (e.g., statins) and can mediate transporter-mediated drug-drug-interactions (DDIs). Bortezomib is the first-in-class proteasome inhibitor drug approved by the U. S. Food and Drug Administration for the treatment of multiple myeloma. The potential of bortezomib to cause OATP-mediated DDIs has not been assessed. The current study investigated the involvement of the ubiquitin-proteasome system (UPS) in OATP1B1 and OATP1B3 degradation and determined the effects of proteasome inhibitors on OATP1B1- and OATP1B3-mediated transport...
2017: PloS One
https://www.readbyqxmd.com/read/29098502/cadmium-pyrithione-suppresses-tumor-growth-in-vitro-and-in-vivo-through-inhibition-of-proteasomal-deubiquitinase
#20
Xin Chen, Jinjie Wu, Qianqian Yang, Xiaolan Zhang, Peiquan Zhang, Siyan Liao, Zhimin He, Xuejun Wang, Chong Zhao, Jinbao Liu
The ubiquitin-proteasome system (UPS) is indispensable to the protein quality control in eukaryotic cells. Due to the remarkable clinical success of using proteasome inhibitors for clinical treatment of multiple myeloma, it is anticipated that targeting the UPS upstream of the proteasome step be an effective strategy for cancer therapy. Deubiquitinases (DUB) are proteases that remove ubiquitin from target proteins and therefore regulate multiple cellular processes including some signaling pathways altered in cancer cells...
February 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
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