Brittany A Borden, Yasmine Baca, Joanne Xiu, Fabio Tavora, Ira Winer, Benjamin A Weinberg, Ari M VanderWalde, Sourat Darabi, W Michael Korn, Andrew P Mazar, Francis J Giles, Lorin Crawford, Howard Safran, Wafik S El-Deiry, Benedito A Carneiro
Glycogen synthase kinase-3B (GSK-3B), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell cycle regulation, apoptosis, and immune response. Small molecule GSK-3B inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3B, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3B alterations. GSK-3B expression and immune cell infiltrate data was analyzed across cancer types, and PD-L1 expression was compared between GSK-3B-mutated and wild-type tumors...
October 21, 2020: Molecular Cancer Therapeutics
Tsung-Ching Lai, Chih-Yeu Fang, Yi-Hua Jan, Hsiao-Ling Hsieh, Yi-Fang Yang, Chun-Yu Liu, Peter Mu-Hsin Chang, Michael Hsiao
BACKGROUND: Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer. METHODS: A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells...
October 21, 2020: Cell Communication and Signaling: CCS
Maja Köhn, Francesca Salvi, Bernhard Hoermann, Javier Del Pino Garcia, Miriam Fontanillo, Rita Derua, Monique Beullens, Mathieu Bollen, Orsolya Barabas
Phosphoprotein Phosphatase-1 (PP1) is a key player in the regulation of phospho-serine (pSer) and phospho-threonine (pThr) dephosphorylation and is involved in a large fraction of cellular signaling pathways. Aberrant activity of PP1 has been linked to many diseases, including cancer and heart failure. Besides a well-established activity control by regulatory proteins, an inhibitory function for phosphorylation (p) of a Thr residue in the  C -terminal intrinsically disordered tail of PP1 has been demonstrated...
October 21, 2020: Chembiochem: a European Journal of Chemical Biology
Petro Halkowycz, Charles E Grimshaw, Walter Keung, Paul Tanis, Chris Proffitt, Kim Peacock, Ron de Jong, Mark Sabat, Urmi Banerjee, Jacques Ermolieff
Two different signaling pathways lead to the activation of the transcription factor NF-κB, initiating distinct biological responses: The canonical NF-κB pathway activation has been implicated in host immunity and inflammatory responses, whereas the noncanonical pathway activation has been involved in lymphoid organ development and B-cell maturation, as well as in the development of chronic inflammatory diseases and some hematologic cancers. The NF-κB-inducing kinase (NIK) is a cytoplasmic Ser/Thr kinase and is a key regulator of the noncanonical pathway...
October 21, 2020: SLAS Discovery
Francesca Fagiani, Stefano Govoni, Marco Racchi, Cristina Lanni
The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts...
October 21, 2020: Molecular Neurobiology
Bo Shen, Aimin Li, Yu-Jui Yvonne Wan, Guijia Shen, Jinshui Zhu, Yuqiang Nie
Objective: The present study examined the role of PPAR β / δ in hepatocellular carcinoma (HCC). Methods: The effect of PPAR β / δ on HCC development was analyzed using PPAR β / δ -overexpressed liver cancer cells and PPAR β / δ -knockout mouse models. Results: PPAR β / δ (-/-) mice were susceptible to diethylnitrosamine- (DEN-) induced HCC (87.5% vs. 37.5%, p < 0.05). In addition, PPAR β / δ -overexpressed HepG2 cells had reduced proliferation, migration, and invasion capabilities accompanied by increased apoptosis and cell cycle arrest at the G0/G1 phase...
2020: BioMed Research International
Anna S Tocheva, Michael Peled, Marianne Strazza, Kieran R Adam, Shalom Lerrer, Shruti Nayak, Inbar Azoulay-Alfaguter, Connor J R Foster, Elliot A Philips, Benjamin Neel, Beatrix Ueberheide, Adam Mor
Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell mediated anti-tumor immunity but many patients do not respond and a significant proportion develops inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses...
October 19, 2020: Journal of Biological Chemistry
Ting-Ting Li, Hai-Bin Zhu
Liver kinase B1 (LKB1) is an essential serine/threonine kinase frequently associated with Peutz-Jeghers syndrome (PJS). In this review, we provide an overview of the role of LKB1 in conferring protection to cancer cells against metabolic stress and promoting cancer cell survival and invasion. This carcinogenic effect contradicts the previous conclusion that LKB1 is a tumor suppressor gene. Here we try to explain the contradictory effect of LKB1 on cancer from a metabolic perspective. Upon deletion of LKB1, cancer cells experience increased energy as well as oxidative stress, thereby causing genomic instability...
October 14, 2020: Biomedicine & Pharmacotherapy
Melanie Dzulko, Miriam Pons, Andreas Henke, Günter Schneider, Oliver H Krämer
Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase. This enzyme is involved in a plethora of cellular processes, including apoptosis, autophagy, cell proliferation, and DNA repair. Remarkably, PP2A can act as a context-dependent tumor suppressor or promoter. Active PP2A complexes consist of structural (PP2A-A), regulatory (PP2A-B), and catalytic (PP2A-C) subunits. The regulatory subunits define the substrate specificity and the subcellular localization of the holoenzyme. Here we condense the increasing evidence that the PP2A B-type subunit PR130 is a critical regulator of cell identity and oncogenic transformation...
October 14, 2020: Biochimica et Biophysica Acta. Reviews on Cancer
Xianghua Zhang, Ji Eun Park, Eun Ho Kim, Jihee Hong, Ki-Tae Hwang, Young A Kim, Chang-Young Jang
Dramatic cellular reorganization in mitosis critically depends on the timely and temporal phosphorylation of a broad range of proteins, which is mediated by the activation of the mitotic kinases and repression of counteracting phosphatases. The mitosis-to-interphase transition, which is termed mitotic exit, involves the removal of mitotic phosphorylation by protein phosphatases. Although protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) drive this reversal in animal cells, the phosphatase network associated with ordered bulk dephosphorylation in mitotic exit is not fully understood...
October 16, 2020: Cellular and Molecular Life Sciences: CMLS
Florian Moik, Wei-Shin Evelyn Chan, Sarah Wiedemann, Christoph Hoeller, Felix Tuchmann, Marie-Bernadette Aretin, Thorsten Fuereder, Sabine Zöchbauer-Müller, Matthias Preusser, Ingrid Pabinger, Cihan Ay
The risk of venous and arterial thromboembolism (VTE/ATE) associated with immune checkpoint inhibitors is currently unclear, and clinical trials evaluating these agents in patients with cancer did not provide information. Our aim was to quantify risk of VTE/ATE in a cohort of patients treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with an immune checkpoint inhibitor at the Medical University of Vienna from 2015-2018 were identified using the in-house pharmacy records (n=672; most frequent entities: 30...
October 16, 2020: Blood
Shile Huang
The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this special issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer...
October 13, 2020: Cells
Xiangyu Wang, Fengmian Wang, Zhi-Gang Zhang, Xiao-Mei Yang, Rong Zhang
Serine/threonine protein kinase-3 (STK3) is a critical molecule of the Hippo pathway but little is known about its biological functions in the ovarian cancer development. We demonstrated the roles of STK3 in ovarian cancer. Existing databases were used to study the expression profile of STK3. STK3 was significantly downregulated in OC patients, and the low STK3 expression was correlated with a poor prognosis. In vitro cell proliferation, apoptosis, and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the roles of STK3...
2020: Journal of Immunology Research
Bashan Zhang, Fei Li, Zinian Zhu, Aijiao Ding, Jintong Luo
Background: Hepatocellular carcinoma (HCC) is a common lethal malignant tumor worldwide. Circular RNAs (circRNAs) have been reported to affect the development of human cancers, including HCC. In this project, we aim to clarify the functional effect of circular CDR1as (circ_CDR1as) on HCC progression. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot is implemented to detect the expression of circ_CDR1as, microRNA (miR)-1287 and Raf-1 proto-oncogene, serine/threonine kinase (Raf1)...
2020: Cancer Management and Research
Jae-Hong Kim, Yeojin Seo, Myungjin Jo, Hyejin Jeon, Young-Seop Kim, Eun-Jung Kim, Donggun Seo, Won-Ha Lee, Sang Ryong Kim, Nozomu Yachie, Quan Zhong, Marc Vidal, Frederick P Roth, Kyoungho Suk
Kinases are critical components of intracellular signaling pathways and have been extensively investigated in regards to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions...
October 15, 2020: Journal of Biological Chemistry
You-Cheng Hseu, Yu-Chi Chiang, Yugandhar Vudhya Gowrisankar, Kai-Yuan Lin, Sheng-Teng Huang, Sirjana Shrestha, Geng-Ruei Chang, Hsin-Ling Yang
Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods...
October 12, 2020: Cancers
Zlata Vershinin, Michal Feldman, Dan Levy
P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts with and methylates PAK4 at chromatin in mammalian cells, leading to activation of the Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion...
October 13, 2020: Scientific Reports
Eun Yeong Lim, Joon Park, Yun Tai Kim, Min Jung Kim
Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway...
October 11, 2020: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Marco Gaviraghi, Andrea Rabellino, Annapaola Andolfo, Matthias Brand, Chiara Brombin, Paola Bagnato, Giuseppina De Feudis, Andrea Raimondi, Alberta Locatelli, Daniela Tosoni, Davide Mazza, Luca Gianni, Giovanni Tonon, Yosef Yarden, Carlo Tacchetti, Tiziana Daniele
ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor...
October 9, 2020: Scientific Reports
Pu Rum Kim, Songjing Zhang, Muhammad Bakhait Rahmat, Cheng-Gee Koh
Protein phosphorylation and dephosphorylation govern intracellular signal transduction and cellular functions. Kinases and phosphatases are involved in the regulation and development of many diseases such as Alzheimer's, diabetes, and cancer. While the functions and roles of many kinases, as well as their substrates, are well understood, phosphatases are comparatively less well studied. Recent studies have shown that rather than acting on fewer and more distinct substrates like the kinases, phosphatases can recognize specific phosphorylation sites on many different proteins, making the study of phosphatases and their substrates challenging...
October 9, 2020: Cell Death & Disease
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