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DOE OSTI2025

Neutron diffraction reveals protonation states in pyridoxal‐5′‐phosphate‐free and glycine external aldimine‐bound serine hydroxymethyltransferase

Serine hydroxymethyltransferase (SHMT) is a critical enzyme in the one-carbon (1C) metabolism pathway catalyzing the reversible conversion of L-Ser into Gly and concurrent transfer of 1C unit to tetrahydrofolate (THF) to give 5,10-methylene-THF (5,10-MTHF), which is used in the downstream syntheses of biomolecules critical for cell proliferation. The cellular 1C metabolism is hijacked by many cancer types to support cancer cell proliferation, making SHMT a promising target for the design and development of novel small-molecule antimetabolite chemotherapies. To advance structure-assisted drug design, knowledge of SHMT catalysis is crucial, but can only be fully realized when the atomic details of each reaction step governed by the acid–base catalysis are elucidated by visualizing active site hydrogen atoms. Here, we used room-temperature neutron crystallography to directly determine protonation states in Thermus thermophilus SHMT (TthSHMT), capturing protomer A in the apo form lacking the coenzyme pyridoxal 5′-phosphate (PLP), and protomer B as a ternary complex with PLP–Gly-external aldimine and (6S)-5-methyltetrahydrofolate (5MTHF). We observed protonation of the Schiff base nitrogen in PLP–Gly and neutrality of the catalytic Lys226 side chain in the ternary complex, whereas Lys226 is protonated and positively charged in the apo-active site. Furthermore, we obtained an X-ray structure of TthSHMT in complex with the substrate THF, which binds identically as 5MTHF at the peripheral binding site. In conclusion, the unique structural and functional information provided by neutron crystallography, in combination with X-ray structures, can be employed in the rational design of SHMT inhibitors.

X-ray crystallography↗

DOE OSTI2021

GRIM-19 inhibits proliferation and induces apoptosis in a p53-dependent manner in colorectal cancer cells through the SIRT7/PCAF/MDM2 axis

Colorectal cancer (CRC) is the leading deadly cancer worldwide. Gene associated with retinoid-IFN-induced mortality-19 (GRIM-19), a novel tumor suppressor, has been reported to be expressed at low levels in human CRC. However, the role of GRIM-19 in CRC progression and the corresponding detailed mechanisms are unclear. The results of this study indicated that GRIM-19 expression is related to CRC progression. Overexpression of GRIM-19 was found to inhibit CRC cell proliferation and induce apoptosis in vitro and in vivo. Our results demonstrated that GRIM-19 suppresses CRC through posttranslational regulation of p53, in which SIRT7 is activated by GRIM-19 and triggers PCAF-mediated MDM2 ubiquitination, eventually stabilizing the p53 protein. We also observed that GRIM-19 enhances the effect of oxaliplatin against CRC. In conclusion, GRIM-19 plays an important role in CRC development and is a potential biomarker and therapeutic target for clinical treatment of CRC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

A synthetic cell density signal can drive proliferation in chick embryonic tendon cells and tendon cells from a full size rooster can produce high levels of procollagen in cell culture

Cell density signaling drives tendon morphogenesis by regulating both procollagen production and cell proliferation. The signal is composed of a small, highly conserved protein (SNZR P) tightly bound to a tissue-specific, unique lipid (SNZR L). This allows the complex (SNZR PL) to bind to the membrane of the cell and locally diffuse over a radius of ~1 mm. The cell produces low levels of this signal but the binding to the membrane increases with the number of tendon cells in the local environment. In this article SNZR P was produced in E.coli and SNZR L was chemically synthesized. The two bind together when heated to 60 °C in the presence of Ca ++ and Mg ++ and the synthesized SNZR PL at ng/ml levels can replace serum. Adding SNZR PL to the medium was also tested on primary tendon cells from adult roosters. The older cells were in a maintenance state in vivo and in cell culture they proliferate more slowly than embryonic cells. Nevertheless, after reaching a moderately high cell density, they produced high levels of procollagen similar to the embryonic cells. This data was not expected from older cells but suggests that adult tendon cells can regenerate the tissue after injury when given the correct signals.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Lymphocytic microparticles suppress retinal angiogenesis via targeting Müller cells in the ischemic retinopathy mouse model

Highlights: F0B7 • LMPs possess strong angiogenesis-inhibiting properties. F0B7 • LMPs suppress Müller cell-derived angiogenic/chemoattractant factors. F0B7 • LMPs attenuate pathological retinal NV and the infiltration of macrophages in vivo. F0B7 • LMPs downregulate ERK1/2 and HIF-1α both in vitro and in vivo. Retinopathy of prematurity (ROP) is the primary cause of visual impairment and vision loss in premature infants, which results from the formation of aberrant retinal neovascularization (NV). An emerging body of evidence has shown that Müller cells are the predominant source of vascular endothelial growth factor (VEGF), which also serves as a chemoattractant for monocyte/macrophage lineage. The recruitment of macrophages is increased during retinal NV, and they exert a pro-angiogenic role in ROP. We have shown that lymphocytic microparticles (microvesicles; LMPs) derived from apoptotic human T lymphocytes possess strong angiogenesis-inhibiting properties. Here, we investigated the effect of LMPs on the chemotactic capacity of Müller cells in vitro using rat Müller cell rMC-1 and mouse macrophage RAW 264.7. In addition, the impact of LMPs was determined in vivo using a mouse model of oxygen-induced ischemic retinopathy (OIR). The results revealed that LMPs were internalized by rMC-1 and reduced their cell proliferation dose-dependently without inducing cell apoptosis. LMPs inhibited the chemotactic capacity of rMC-1 on RAW 264.7 via reducing the expression of VEGF. Moreover, LMPs attenuated pathological retinal NV and the infiltration of macrophages in vivo. LMPs downregulated ERK1/2 and HIF-1α both in vitro and in vivo. These findings expand our understanding of the effects of LMPs, providing evidence of LMPs as a promising therapeutic approach for the treatment of retinal NV diseases.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

YAP/STAT3 promotes the immune escape of larynx carcinoma by activating VEGFR1-TGFβ signaling to facilitate PD-L1 expression in M2-like TAMs

Larynx carcinoma (LC) is the most prevalent head and neck cancer among adults. LC xenograft mouse model was generated to verify the effect of VEGF on macrophage polarization and tumor growth in vivo. EdU assay was performed to measure the cell proliferation. Transwell assay was applied to assess cell migration. The expression of YAP and STAT3 was also significantly increased in LC tumor tissues. Moreover, both YAP and STAT3 overexpression in LC cells promoted the proliferation, migration, as well as the secretion of PD-L1 in M2-like TAMs. Mechanistically, the interaction between YAP and STAT3 facilitated the transcription of VEGF. Moreover, with a co-culture system, VEGF secretion in LC cells enhanced PD-L1 expression in M2-like TAMs via activating VEGFR1-TGFβ signaling pathway. Furthermore, VEGF secreted from LC cells also promoted the tumor growth of LC in vivo. We revealed that dysregulated YAP/STAT3 activity in LC cells could enhance the secretion of VEGF, which then functioned on M2-like TAMs via activating VEGFR1-TGFββ pathway to promote the expression of PD-L1 and immunosuppressive function of M2-like TAMs. Therefore, VEGF and PD-L1 might have a pivotal crosstalk between M2-like TAMs and LC cells, which provided a novel therapeutic target in regulating the metastasis of LC in future.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Grape ASR Regulates Glucose Transport, Metabolism and Signaling

To decipher the mediator role of the grape Abscisic acid, Stress, Ripening (ASR) protein, VvMSA, in the pathways of glucose signaling through the regulation of its target, the promoter of hexose transporter VvHT1, we overexpressed and repressed VvMSA in embryogenic and non-embryogenic grapevine cells. The embryogenic cells with organized cell proliferation were chosen as an appropriate model for high sensitivity to the glucose signal, due to their very low intracellular glucose content and low glycolysis flux. In contrast, the non-embryogenic cells displaying anarchic cell proliferation, supported by high glycolysis flux and a partial switch to fermentation, appeared particularly sensitive to inhibitors of glucose metabolism. By using different glucose analogs to discriminate between distinct pathways of glucose signal transduction, we revealed VvMSA positioning as a transcriptional regulator of the glucose transporter gene VvHT1 in glycolysis-dependent glucose signaling. The effects of both the overexpression and repression of VvMSA on glucose transport and metabolism via glycolysis were analyzed, and the results demonstrated its role as a mediator in the interplay of glucose metabolism, transport and signaling. The overexpression of VvMSA in the Arabidopsis mutant abi8 provided evidence for its partial functional complementation by improving glucose absorption activity.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Bioenergy sorghum nodal root bud development: morphometric, transcriptomic and gene regulatory network analysis

Bioenergy sorghum’s large and deep nodal root system and associated microbiome enables uptake of water and nutrients from and deposition of soil organic carbon into soil profiles, key contributors to the crop’s resilience and sustainability. The goal of this study was to increase our understanding of bioenergy sorghum nodal root bud development. Sorghum nodal root bud initiation was first observed on the stem node of the 7 th phytomer below the shoot apex. Buds were initiated near the upper end of the stem node pulvinus on the side of the stem opposite the tiller bud, then additional buds were added over the next 6-8 days forming a ring of 10-15 nascent nodal root buds around the stem. Later in plant development, a second ring of nodal root buds began forming on the 17 th stem node immediately above the first ring of buds. Overall, nodal root bud development can take ~40 days from initiation to onset of nodal root outgrowth. Nodal root buds were initiated in close association with vascular bundles in the rind of the pulvinus. Stem tissue forming nascent nodal root buds expressed sorghum homologs of genes associated with root initiation (WOX4), auxin transport (LAX2, PIN4), meristem activation (NGAL2), and genes involved in cell proliferation. Expression of WOX11 and WOX5, genes involved in root stem niche formation, increased early in nodal root bud development followed by genes encoding PLTs, LBDs (LBD29), LRP1, SMB, RGF1 and root cap LEAs later in development. A nodal root bud gene regulatory network module expressed during nodal root bud initiation predicted connections linking PFA5, SPL9 and WOX4 to genes involved in hormone signaling, meristem activation, and cell proliferation. A network module expressed later in development predicted connections among SOMBRERO, a gene involved in root cap formation, and GATA19, BBM, LBD29 and RITF1/RGF1 signaling. Overall, this study provides a detailed description of bioenergy sorghum nodal root bud development and transcriptome information useful for understanding the regulation of sorghum nodal root bud formation and development.

09 BIOMASS FUELS↗

DOE OSTI2021

The UPR regulator IRE1 promotes balanced organ development by restricting TOR-dependent control of cellular differentiation in Arabidopsis

Proteostasis of the endoplasmic reticulum (ER) is controlled by sophisticated signaling pathways that are collectively called the unfolded protein response (UPR) and are initiated by specialized ER membrane-associated sensors. The evidence that complete loss-of-function mutations of the most conserved of the UPR sensors, inositol-requiring enzyme 1 (IRE1), dysregulates tissue growth and development in metazoans and plants raises the fundamental question as to how IRE1 is connected to organismal growth. To address this question, we interrogated the Arabidopsis primary root, an established model for organ development, using the tractable Arabidopsis IRE1 mutant ire1a ire1b, which has marked root development defects in the absence of exogenous stress. We demonstrate that IRE1 is required to reach maximum rates of cell elongation and root growth. We also established that in the actively growing ire1a ire1b mutant root tips the Target of Rapamycin (TOR) kinase, a widely conserved pro-growth regulator, is hyperactive, and that, unlike cell proliferation, the rate of cell differentiation is enhanced in ire1a ire1b in a TOR-dependent manner. By functionally connecting two essential growth regulators, these results underpin a novel and critical role of IRE1 in organ development and indicate that, as cells exit an undifferentiated state, IRE1 is required to monitor TOR activity to balance cell expansion and maturation during organ biogenesis.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Deuterium Concentration Effects on Cell Cycle Progression

Deuterium (D) seems to play an important role in biology and is thought to be a missing piece in understanding cancer and radiation resistance. D is found in natural water at a concentration of ~150 parts per million (ppm), while D concentrations above 150 ppm are known to produce toxic effects in many organisms. There is evidence to suggest D levels significantly less than 150 ppm can cause delays in cell progression through the normal mitotic cell cycle. Some have theorized that the deuterium: hydrogen ratio (D:H) in cells may impact radiation resistance. Therefore, evaluating the role of D in human cells should lead to a better understanding of cell cycle progression and radiation resistance. To date, little has been revealed on the time-dependent effects of deuterium-depleted water (DDW – less than 150 ppm) on normal and cancer human cells or how the reduction of cell proliferation is associated with cell cycle regulation and consequence on gene expression profiles. Our studies will help further the mission of the Department of Energy to enhance the understanding of deuterium in fundamental biology by studying the cell cycle as a function of D concentration.

36 MATERIALS SCIENCE↗

DOE OSTI2021

Deuterium Concentration Effects on Cell Cycle Progression

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

AFF4 facilitates melanoma cell progression by regulating c-Jun activity

Melanoma is characterized by high mortality and poor prognosis due to metastasis. AFF4 (AF4/FMR2 family member 4), as a scaffold protein, is a component of the super elongation complex (SEC), and is involved in the progression of tumors, e.g., leukemia, head and neck squamous cell carcinoma (HNSCC). However, few studies on AFF4 have focused on melanoma. Here, AFF4 expression levels and clinicopathological features were evaluated in melanoma tissue samples. Then, we performed cell proliferation, migration and invasion assays in A375 and A2058 cells lines in vitro to evaluate the role of AFF4 in melanoma. The effects of AFF4 knockdown in vivo were characterized via a xenograft mouse model. Finally, the correlation between c-Jun and AFF4 protein levels in melanoma was analyzed by rescue assay and immunohistochemistry (IHC). We found that AFF4 expression was upregulated in melanoma tumor tissues and that AFF4 protein expression was also closely related to the prognosis of patients with cutaneous melanoma. Moreover, AFF4 could promote the invasion and migration of melanoma cells by mediating epithelial to mesenchymal transition (EMT). AFF4 might regulate c-Jun activity to promote the invasion and migration of melanoma cells. Importantly, c-Jun was regulated by the AFF4 promoted melanoma tumorigenesis in vivo. Taken together, AFF4 may be a novel oncogene that promotes melanoma progression through regulation of c-Jun activity.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma

Melanoma, which originates from neural crest derived melanocytes, causes severe pain and even death to numerous patients. Previous studies reported that Notchless Homolog 1 (NLE1) plays an important role in cell proliferation, transcription and signal transduction. However, the clinical significance and biological behavior of NLE1 in melanoma remain a mystery. Thus, the role of NLE1 in melanoma was investigated in vitro and in vivo. The expression of NLE1 in melanoma was elevated and the expression level was positively correlated with lymphatic metastasis and tumor stage. In addition, NLE1 knockdown by shRNA specifically inhibited proliferation, enhanced the apoptotic sensitivity and hindered migration of melanoma cells in vitro. Mice xenograft model further showed that NLE1 knockdown could inhibit the tumor formation of melanoma in vivo. Additionally, the induction of apoptosis of melanoma cells by NLE1 knockdown required the participation of a series of apoptosis-related proteins. Besides, NLE1 can activate the PI3K/AKT signaling pathway. In summary, NLE1 was involved in the development and progression of melanoma, which may be a novel potential target for molecular therapy of melanoma.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Karyopherin beta 1 (Kpnβ1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpnβ1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpnβ1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpnβ1 and its cargoes, NFκB/p65, NFAT and AP-1, and the overexpression of Kpnβ1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpnβ1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Downregulation of fascin in the first trimester placental villi is associated with early recurrent miscarriage

Highlights: • Fascin is downregulated in the placentae of pregnancies complicated by early recurrent miscarriage. • Knockdown of fascin decreased HTR-8/SVneo cells' proliferation, migration and invasion. • Fascin knockdown decreased phosphorylated ERK1/2 and phosphorylated STAT3 protein level in HTR-8/SVneo cells. • Hypoxia reoxygenation decreased fascin, N-Cadherin and Vimentin protein levels to affect HTR-8/SVneo cells' invasion. Inadequate trophoblast proliferation, shallow invasion and exaggerated rate of trophoblast apoptosis are implicated in early recurrent miscarriage (ERM). However, the mechanistic bases of this association have not been fully established. We aimed at investigating the involvement of fascin, an actin-bundling protein, in trophoblast activities and ERM. We found that fascin was downregulated in the cytotrophoblasts (CTBs) and distal cytotrophoblasts (DCTs) of ERM placentae. Knockdown of fascin altered cellular and nucleolar morphology, and inhibited the proliferation but increased apoptosis of trophoblastic HTR8/SVneo cells. Furthermore, fascin knockdown decreased the expression of transcription factors such as Snail1/2, Twist and Zeb1/2, mesenchymal molecules such as Vimentin and N-cadherin, and the protein expression of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylates signal transducer and activator of transcript 3 (STAT3). Exposure of HTR-8/SVneo cells to hypoxia reoxygenation (H/R) decreased fascin expression to affect the cells’ invasion. Our results indicate for the first time that the downregulation of fascin is involved in the pathogenesis of early recurrent miscarriage; and hence a potential therapeutic target against the disease.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Phenotypical modifications of immune cells are enhanced by extracellular matrix

Immune cells not only constitute tumour microenvironment but they may even affect disease prognosis as a result of dual functional roles that they may play in tumour tissues. Two frequently used established immune cell lines (lymphocytic Jurkat and monocytic THP-1) were used to test whether microenvironmental factors, especially molecular components of extracellular matrix, can shape the phenotype of immune cells. Proliferation, morphological and phenotypical analyses were applied to compare behaviour of the immune cells, typically cultured as suspensions in culture medium, with their behaviour in collagen type I-based and Matrigel-based 3D cultures. Density of both immune cell types in routine suspension cultures affected their subsequent proliferation in extracellular matrices. THP-1 cells appeared to be more sensitive to their surrounding microenvironment as judged from extracellular matrix type-dependent changes in their cell doubling times and from slight increase in their diameters in both extracellular matrix-containing cell cultures. Moreover, even chemically uninduced monocytic THP-1 cells were present in a minor fraction as CD68 positive cell population in collagen type I matrix indicating their partial differentiation to macrophages. Observed modifications of immune cells by microenvironmental factors may have profound implications for their roles in healthy and pathological tissues.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

LncRNA ZFAS1 promotes invasion of medullary thyroid carcinoma by enhancing EPAS1 expression via miR‐214‐3p/UCHL1 axis

Abstract lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential function of this lncRNA in MTC by investigating the involvement of the lncRNA ZFAS1 in a ceRNA network that regulates MTC invasion. Proliferation, invasion, and migration of cells were evaluated using EdU staining and Transwell assays. Immunoprecipitation (IP) assays, dual‐fluorescence reporter, and RNA IP assays were employed to examine the binding interaction among genes. Nude mice were used to explore the role of lncRNA ZFAS1 in MTC in vivo. ZFAS1 and EPAS1 were upregulated in MTC. Silencing ZFAS1 inhibited MTC cell proliferation and invasion under hypoxic conditions, which reduced EPAS1 protein levels. UCHL1 knockdown increased EPAS1 ubiquitination. ZFAS1 positively regulated UCHL1 expression by binding to miR‐214‐3p. Finally, silencing ZFAS1 significantly repressed tumor formation and metastasis in MTC. LncRNA ZFAS1 promotes invasion of MTC by upregulating EPAS1 expression via the miR‐214‐3p/UCHL1 axis.

Chen, Wenjing↗

DOE OSTI2022

Physical Models from Physical Templates Using Biocompatible Liquid Crystal Elastomers as Morphologically Programmable Inks For 3D Printing

Advanced manufacturing has received considerable attention as a tool for the fabrication of cell scaffolds however, finding ideal biocompatible and biodegradable materials that fit the correct parameters for 3D printing and guide cells to align remain a challenge. Herein, a photocrosslinkable smectic-A (Sm-A) liquid crystal elastomer (LCE) designed for 3D printing is presented, that promotes cell proliferation but most importantly induces cell anisotropy. The LCE-based bio-ink allows the 3D duplication of a highly complex brain structure generated from an animal model. Vascular tissue models are generated from fluorescently stained mouse tissue spatially imaged using confocal microscopy and subsequently processed to create a digital 3D model suitable for printing. The 3D structure is reproduced using a Digital Light Processing (DLP) stereolithography (SLA) desktop 3D printer. Synchrotron Small-Angle X-ray Diffraction (SAXD) data reveal a strong alignment of the LCE layering within the struts of the printed 3D scaffold. The resultant anisotropy of the LCE struts is then shown to direct cell growth. This study offers a simple approach to produce model tissues built within hours that promote cellular alignment.

3D cell culture↗

DOE OSTI2025

How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations

Oncogenic KRAS mutations impair GTP hydrolysis and increase the active GTP-bound KRAS population, which leads to growth-factor-independent cell proliferation and survival of cancer cells. Despite notable successes of small-molecule inhibitors in the treatment of KRASG12C cancer, many of these small-molecule inhibitors preferentially bind to inactive (GDP-bound) mutant KRAS, whose availability is limited by the slow rate of intrinsic GTP hydrolysis. A better understanding of how KRAS mutations impair intrinsic hydrolysis is important for designing more effective small-molecule therapeutics. In this work, experimental and computational approaches were utilized to investigate how the most important oncogenic mutations affect the intrinsic hydrolysis of GTP. Here, we found that Q61H, G12V, and G12R mutations impair intrinsic hydrolysis by around 7-fold, 9-fold, and more than 20-fold, respectively, whereas G12A, G12C, G12D, and G13D have less effect. Based on mechanistic investigations, we propose that KRAS mutations impair intrinsic hydrolysis by disrupting the interactions needed to align the nucleophilic water molecule with GTP for nucleophilic attack. These results can assist small-molecule inhibitor design and also benefit the development of other therapeutic strategies, such as rescuing hydrolysis.

Ab Initio↗