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Endosomal cancer

Akari Murakami, Masashi Maekawa, Katsuhisa Kawai, Jun Nakayama, Nobukazu Araki, Kentaro Semba, Tomohiko Taguchi, Yoshiaki Kamei, Yasutsugu Takada, Shigeki Higashiyama
Rho GTPase Rac1 is a central regulator of F-actin organization and signal transduction to control plasma membrane dynamics and cell proliferation. Dysregulated Rac1 activity is often observed in various cancers including breast cancer, and is suggested to be critical for malignancy. Here, we showed that the ubiquitin E3 ligase complex Cullin-3 (CUL3)/KCTD10 is essential for epidermal growth factor (EGF)-induced/HER2-dependent Rac1 activation in HER2-positive breast cancer cells. EGF-induced dorsal membrane ruffle formation and cell proliferation that depends on both Rac1 and HER2 were suppressed in CUL3- or KCTD10-depleted cells...
December 4, 2018: Cancer Science
Marta Portela, Berta Segura-Collar, Irene Argudo, Almudena Sáiz, Ricardo Gargini, Pilar Sánchez-Gómez, Sergio Casas-Tintó
Genetic lesions in glioblastoma (GB) include constitutive activation of PI3K and EGFR pathways to drive cellular proliferation and tumor malignancy. An RNAi genetic screen, performed in Drosophila melanogaster to discover new modulators of GB development, identified a member of the secretory pathway: kish/TMEM167A. Downregulation of kish/TMEM167A impaired fly and human glioma formation and growth, with no effect on normal glia. Glioma cells increased the number of recycling endosomes, and reduced the number of lysosomes...
December 2, 2018: Glia
David Novo, Nikki Heath, Louise Mitchell, Giuseppina Caligiuri, Amanda MacFarlane, Dide Reijmer, Laura Charlton, John Knight, Monika Calka, Ewan McGhee, Emmanuel Dornier, David Sumpton, Susan Mason, Arnaud Echard, Kerstin Klinkert, Judith Secklehner, Flore Kruiswijk, Karen Vousden, Iain R Macpherson, Karen Blyth, Peter Bailey, Huabing Yin, Leo M Carlin, Jennifer Morton, Sara Zanivan, Jim C Norman
Mutant p53s (mutp53) increase cancer invasiveness by upregulating Rab-coupling protein (RCP) and diacylglycerol kinase-α (DGKα)-dependent endosomal recycling. Here we report that mutp53-expressing tumour cells produce exosomes that mediate intercellular transfer of mutp53's invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53's ability to control production of the sialomucin, podocalyxin, and activity of the Rab35 GTPase which interacts with podocalyxin to influence its sorting to exosomes...
November 29, 2018: Nature Communications
Jin Ma, Ke Kang, Yujia Zhang, Qiangying Yi, Zhongwei Gu
In this work, we presented the ternary nanoparticles [pCBMA(CD-D/DOX)] based on peptide dendritic carbon dots (CDs) to realize tumor-specific drug delivery and high efficient cancer therapy. The versatile nanoparticles could achieve "stealth" delivery in blood due to the anti-fouling zwitterion coating. Meanwhile, charge changes of the zwitterions could be moderated during their transportation toward/inside tumor cells, where subtle environmental pH variations acted as potent stimuli to actualize desired functions...
November 26, 2018: ACS Applied Materials & Interfaces
Sumi Sung, Jieun Kim, Youngmi Jung
The liver has a wide range of physiological functions in the body, and its health is maintained by complex cross-talk among hepatic cells, including parenchymal hepatocytes and nonparenchymal cells. Exosomes, which are one method of cellular communication, are endosomal-derived small vesicles that are released by donor cells and delivered to the target cells at both short and long distances. Because exosomes carry a variety of cargoes, including proteins, mRNAs, microRNAs and other noncoding RNAs originating from donor cells, exosomes convey cellular information that enables them to potentially serve as biomarkers and therapeutics in liver diseases...
November 22, 2018: International Journal of Molecular Sciences
Sanaz Javanmardi, Mahmoud Reza Aghamaali, Samira Sadat Abolmaali, Ali Mohammad Tamaddon
MicroRNAs are small noncoding RNAs that have key roles in gene expression. In recent decades, it has been revealed that aberrant expression of microRNAs is related to abnormality in gene expression and it is believed that they have potential to be used as anti-cancer drugs. However, the delivery of these small molecules is limited due to some obstacles including low uptake and insufficient endosomal release, intracellular nucleases degradation, phagocytic elimination and renal filtration. To overcome these issues, there are many novel delivery systems developed to improve efficiency of microRNAs therapy ranged from viral to synthetic; some are further developed with targeted ligands for active targeting purposes...
November 20, 2018: Current Pharmaceutical Design
Jiajia Xiang, Xin Liu, Zhuxian Zhou, Dingcheng Zhu, Quan Zhou, Ying Piao, Liming Jiang, Jianbin Tang, Xiangrui Liu, Youqing Shen
The application of non-viral gene vectors has been limited by their insufficient transfection efficiency because of poor serum stability, high endosomal entrapment, limited intracellular release and low accumulation in the targeted organelle. It has been still challenging to design gene carriers with properties that can overcome all the barriers. We previously developed a ROS-responsive cationic polymer, poly[(2-acryloyl)ethyl(p-boronic acid benzyl) diethylammonium bromide] (B-PDEAEA), which switches the charge at high concentrations of intracellular ROS to promote intracellular DNA release...
November 22, 2018: ACS Applied Materials & Interfaces
Soo Jeong Park, Jeong Mi Kim, Jihyo Kim, Jaehark Hur, Sun Park, Kyongmin Kim, Ho-Joon Shin, Yong-Joon Chwae
Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called "apoptotic exosome-like vesicles" (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors...
November 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ian P Harrison, Antony Vinh, Ian R D Johnson, Raymond Luong, Grant R Drummond, Christopher G Sobey, Tony Tiganis, Elizabeth D Williams, John J O' Leary, Doug A Brooks, Stavros Selemidis
Reactive oxygen species (ROS) promote growth factor signalling including for VEGF-A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, the subcellular localization of ROS production and cellular targets in vivo that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue...
October 23, 2018: Oncotarget
Priyanka Ray, Matthew Confeld, Pawel Borowicz, Tao Wang, Sanku Mallik, Mohiuddin Quadir
A pH-responsive nanoparticle platform, based on PEG-b-poly (carbonate) block copolymers have been proposed that can respond to low pH as found in many cancer micro- and intracellular environment, including that in pancreatic cancer. The hydrophobic domain, i.e., the poly (carbonate) segment has been substituted with tertiary amine side chains, such as N, N'-dibutylethylenediamine (pKa = 4.0, DB) and 2-pyrrolidin-1-yl-ethyl-amine (pka = 5.4, Py) to generate two different sets of block copolymers namely PEG-DB and PEG-PY systems...
October 28, 2018: Colloids and Surfaces. B, Biointerfaces
Sarah A Otieno, Samuel Z Hanz, Bianca Chakravorty, Anqi Zhang, Lukas M Klees, Ming An, Wei Qiang
The applications of the pH low insertion peptide (pHLIP) in cancer diagnosis and cross-membrane cargo delivery have drawn increasing attention in the past decade. With its origin as the transmembrane (TM) helix C of bacteriorhodopsin, pHLIP is also an important model for understanding how pH can affect the folding and topogenesis of a TM α-helix. Protonations of multiple D/E residues transform pHLIP from an unstructured coil at membrane surface (known as state II, at pH ≥ 7) to a TM α-helix (state III, pH ≤ 5...
November 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
De-E Liu, Jinxia An, Chengcai Pang, Xiangjie Yan, Wei Li, Jianbiao Ma, Hui Gao
High transfection efficiency and superior cell imaging are required for cationic polymers-based gene delivery system to afford high therapeutic effect but its high toxicity and unstable cell imaging are easily ignored. In this study, cationic amino poly(glycerol methacrylate) derivative (PGMA-EDA) is used to incorporate bovine serum albumin (BSA) and aggregation-induced emission (AIE) molecular (tetraphenylethylene derivatives, TPE) as an efficient carrier for gene transfection and intracellular imaging. The obtained polymer/pDNA-TPE/BSA (PDTB) quaternary nanoparticles (NPs) not only exhibit efficient gene transfection but also show excellent biocompatibility...
November 14, 2018: Macromolecular Bioscience
Kendra A Bussey, Sripriya Murthy, Elisa Reimer, Baca Chan, Bastian Hatesuer, Klaus Schughart, Britt Glaunsinger, Heiko Adler, Melanie M Brinkmann
Murine gammaherpesvirus 68 (MHV68) is an amenable small animal model for study of the human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal TLR escort protein UNC93B, endosomal TLR7, 9, and 13, and cell surface TLR2 in MHV68 detection. We found that the interferon α (IFNα) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/- cells compared to wildtype (WT), but not completely lost. Tlr7-/- pDC responded similarly to WT...
November 14, 2018: Journal of Virology
Daniel S J Miller, Robert D Bloxham, Ming Jiang, Ilaria Gori, Rebecca E Saunders, Debipriya Das, Probir Chakravarty, Michael Howell, Caroline S Hill
Signal transduction pathways stimulated by secreted growth factors are tightly regulated at multiple levels between the cell surface and the nucleus. The trafficking of cell surface receptors is emerging as a key step for regulating appropriate cellular responses, with perturbations in this process contributing to human diseases, including cancer. For receptors recognizing ligands of the transforming growth factor β (TGF-β) family, little is known about how trafficking is regulated or how this shapes signaling dynamics...
November 13, 2018: Cell Reports
Lara Console, Mariafrancesca Scalise, Cesare Indiveri
Exosomes are endosomal-derived nano-vesicles. They are considered vehicles through which donor cells transfer proteins, lipids and nucleic acids to target cells thus influencing their metabolism. Exosomes are involved in inflammatory processes that play a pivotal role in a large number of pathologic states including cancer, inflammatory bowel diseases, type 2 diabetes, obesity, rheumatoid arthritis and neurodegenerative diseases. The association between inflammation and change in nature or expression level of some exosomal cargos is the fundamental step for identifying possible novel biomarkers of inflammatory-based diseases...
November 9, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Megumi Tatematsu, Kenji Funami, Tsukasa Seya, Misako Matsumoto
RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated...
November 7, 2018: Journal of Innate Immunity
Andrew W Simonson, Atip Lawanprasert, Tyler D P Goralski, Kenneth C Keiler, Scott H Medina
We report the design, synthesis and efficacy of a new class of gel-like nano-carrier, or 'nanogel', prepared via templated electrostatic assembly of anionic hyaluronic acid (HA) polysaccharides with the cationic peptide amphiphile poly-L-lysine (PLL). Small molecules and proteins present during nanogel assembly become directly encapsulated within the carrier and are precisely released by tuning the nanogel HA:PLL ratio to control particle swelling. Remarkably, nanogels exhibit versatile and complimentary mechanisms of cargo delivery depending on the biologic context...
November 3, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
Eun-Ju Hyun, Mohammad Nazmul Hasan, Sung Hun Kang, Sungpil Cho, Yong-Kyu Lee
Oral siRNA delivery is an ideal way to translate siRNA therapeutic effects in the clinic due to its ability to be administered in convenient and multiple dosages. However, an effective oral delivery system requires overcoming both a hostile gastrointestinal (GI) environment and non-specific targeting. Here, an HTsRP-NC system is a new oral siRNA delivery system consisting of a siRNA/protamine (sRP) nano-complex protected by a multi-functional hyaluronic acid-taurocholic acid (HA-TCA) conjugate. The HTsRP-NC promotes cell penetration and enhances endosomal escape in cancer cells...
November 3, 2018: International Journal of Pharmaceutics
Pablo Sánchez-Martín, Masaaki Komatsu
SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer...
November 5, 2018: Journal of Cell Science
Koyel Chakravarty, D C Dalal
The primary aim of liposomal drug delivery is to wisely modulate the drug delivery system in order to target diseased tissues. Temperature-sensitive liposomes function as a prospective weapon to combat toxic side effects corresponding to direct infusion of anticancer drugs. The main objective of the present study is to model liposomal drug release, subsequent drug transport in solid tumour along with integrated actions of tumour cell surface and endosomal events. Generalized mathematical model for liposomal drug delivery is proposed in which vital physical phenomena, such as kinetics of liposome-encapsulated drug, free drug release from liposomes, transport of both liposomal drug and free drug into the tumour compartment, plasma clearance, protein-drug interactions, drug-tumour cell receptor interactions, internalization of drug through endocytosis along with corresponding endosomal events...
November 1, 2018: Mathematical Biosciences
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