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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL

Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Bcl-2 expression is essential for development and normal physiological properties of tooth hard tissue and saliva production

Background: Apoptosis plays a fundamental role in appropriate tissue development and function. Although expression of Bcl-2 has been reported during tooth and submandibular gland (SMG) development, the physiological role Bcl-2 plays during these processes has not been addressed. This study was performed to evaluate the impact of Bcl-2 expression on the formation and properties of tooth hard tissue, and saliva production. Methods: Twenty-four mice (12 males and 12 females) were divided into three groups of eight (n=8): group A (Bcl-2 +/+), group B (Bcl-2 +/-), and group C (Bcl-2 -/-) and subjected to micro-CT analyses. The mineral content of first molars was analyzed by X-Ray diffraction (XRD) and scanning electron microscopy (SEM) color dot map. The surface microhardness was determined by Vickers test on labial surfaces of incisors. Saliva was collected from different groups of mice after subcutaneous injection of pilocarpine. Results: Samples from Bcl-2 -/- mice showed significantly smaller micro-CT values, lower and poor crystallinity of hydroxyapatite (HA), and lowest surface micro hardness. SMG from Bcl-2 -/- mice showed remarkable reduction in size, consistent with reduced saliva accumulation. Conclusions: The absence of Bcl-2 expression in SMG did not affect the expression of other Bcl-2 family members. Thus, Bcl-2 expression influence on the formation and properties of tooth hard tissue, and saliva accumulation. Significance: Bcl-2 expression has a significant impact on the mineralogical content of enamel crystals of tooth structure. Lack of Bcl-2 expression led to impaired production of enamel ACP crystals. - Highlights: • Lack of Bcl-2 expression led to impaired production of enamel ACP crystals. • Germline deletion of Bcl-2 reduced the surface microhardness of enamel. • Bcl-2 expression is vitally important for SMG function and saliva production. • Lack of Bcl-2 expression was not compensated by expression of other Bcl-2 family members.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Structural basis for the interaction between DJ-1 and Bcl-XL

Highlights: • Oxidized, but not reduced, DJ-1 interacts with Bcl-X{sub L}. • C-terminal α8-helix of DJ-1 acts as a binding motif for Bcl-X{sub L}. • C-terminal α8-helix of DJ-1 binds to the BH3 peptide-binding groove in Bcl-X{sub L}. • A conserved binding mode of the Bcl-X{sub L}/DJ-1 and other Bcl-X{sub L}/BH3 peptide complexes. • Understanding of structural basis for the binding between DJ-1 and Bcl-X{sub L}. DJ-1 is a multifunctional protein associated with Parkinson's disease (PD) and tumorigenesis. In response to ultraviolet B (UVB) irradiation, DJ-1 is translocated into the mitochondria, and its interaction with the mitochondrial protein Bcl-X{sub L} protects cells against death. In this study, we characterized the molecular interaction between DJ-1 and Bcl-X{sub L} by NMR spectroscopy. The NMR chemical shift perturbation data demonstrated that the oxidized but not the reduced form of DJ-1 binds to the predominantly hydrophobic groove surrounded by the BH1–BH3 domains in Bcl-X{sub L}. In addition, our results showed that the C-terminal α8-helix peptide (Cpep) of DJ-1 binds to the pro-apoptotic BH3 peptide-binding hydrophobic groove in Bcl-X{sub L} and, thus, acts as a Bcl-X{sub L}-binding motif. In combination with the NMR chemical shift perturbation data, a refined structural model of the Bcl-X{sub L}/DJ-1 Cpep complex revealed that the binding mode is remarkably similar to that of other Bcl-X{sub L}/pro-apoptotic BH3 peptide complexes. Taken together, our results provide a structural basis for the binding mechanism between DJ-1 and Bcl-X{sub L}, which will contribute to molecular understanding of the role of mitochondrial DJ-1 in Bcl-X{sub L} regulation in response to oxidative stress.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-93-5p suppresses cellular senescence by directly targeting Bcl-w and p21

Highlights: • Overexpression of Bcl-w promoted activities of SA-ß-gal and H3K9me3. • Bcl-w induced expressions of senescence-related proteins. • In this study, we investigated the mechanism of Bcl-w-induced premature cellular senescence in GBM and lung cancer cells. Cellular senescence, a distinctive type of irreversible growth arrest, develops in response to various stimuli. Bcl-w, an oncogene and member of the Bcl-2 family, has been reported to promote tumorigenicity in various cancer cells. Here, we sought to explore the potential role of Bcl-w in premature senescence, which has received relatively little research attention. Our findings demonstrate that Bcl-w enhances the activity of senescence-associated β-galactosidase (SA-β-gal) and promotes histone H3 tri-methylation at lysine 9 (H3K9me3) and expressions of p53, Notch2, p21, and p16—hallmarks of the senescent phenotype—in human U251 glioblastoma and H460 lung carcinoma cells. It is also known that microRNAs (miRNAs) regulate processes related to tumor development, such as cell proliferation, differentiation, survival, metabolism, inflammation, invasion, angiogenesis, and senescence. In this context, we found that miR-93-5p inhibited premature cellular senescence by directly suppressing Bcl-w and p21 expressions. Collectively, these findings suggest that targeting miR-93-5p–regulated Bcl-w may be a useful strategy for preventing premature senescence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

IL-13 in LPS-Induced Inflammation Causes Bcl-2 Expression to Sustain Hyperplastic Mucous cells

Exposure to lipopolysaccharides (LPS) causes extensive neutrophilic inflammation in the airways followed by mucous cell hyperplasia (MCH) that is sustained by the anti-apoptotic protein, Bcl-2. To identify inflammatory factor(s) that are responsible for Bcl-2 expression, we established an organ culture system consisting of airway epithelial tissue from the rat nasal midseptum. The highest Muc5AC and Bcl-2 expression was observed when organ cultures were treated with brochoalveolar lavage (BAL) fluid harvested from rats 10 h post LPS instillation. Further, because BAL harvested from rats depleted of polymorphonuclear cells compared to controls showed increased Bcl-2 expression, analyses of cytokine levels in lavages identified IL-13 as an inducer of Bcl-2 expression. Ectopic IL-13 treatment of differentiated airway epithelial cells increased Bcl-2 and MUC5AC expression in the basal and apical regions of the cells, respectively. When Bcl-2 was blocked using shRNA or a small molecule inhibitor, ABT-263, mucous cell numbers were reduced due to increased apoptosis that disrupted the interaction of Bcl-2 with the pro-apoptotic protein, Bik. Furthermore, intranasal instillation of ABT-263 reduced the LPS-induced MCH in bik +/+ but not bik -/- mice, suggesting that Bik mediated apoptosis in hyperplastic mucous cells. Therefore, blocking Bcl-2 function could be useful in reducing IL-13 induced mucous hypersecretion.

Science & Technology - Other Topics↗
DOE OSTI2019

BCL: A Cross-Platform Distributed Data Structures Library

One-sided communication is a useful paradigm for irregular parallel applications, but most one-sided programming environments, including MPI's one-sided interface and PGAS programming languages, lack application-level libraries to support these applications. We present the Berkeley Container Library, a set of generic, cross-platform, high-performance data structures for irregular applications, including queues, hash tables, Bloom filters and more. BCL is written in C++ using an internal DSL called the BCL Core that provides one-sided communication primitives such as remote get and remote put operations. The BCL Core has backends for MPI, OpenSHMEM, GASNet-EX, and UPC++, allowing BCL data structures to be used natively in programs written using any of these programming environments. Along with our internal DSL, we present the BCL ObjectContainer abstraction, which allows BCL data structures to transparently serialize complex data types while maintaining efficiency for primitive types. We also introduce the set of BCL data structures and evaluate their performance across a number of high-performance computing systems, demonstrating that BCL programs are competitive with hand-optimized code, even while hiding many of the underlying details of message aggregation, serialization, and synchronization.

Brock, Benjamin↗
DOE OSTI2016

Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity

Mammalian target of rapamycin (mTOR) is a therapeutic target for head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the activity of AZD-2014, a potent mTOR complex 1/2 (mTORC1/2) dual inhibitor, against HNSCC cells. We showed that AZD-2014 blocked mTORC1/2 activation in established and primary human HNSCC cells, where it was anti-proliferative and pro-apoptotic. Yet, AZD-2014 was non-cytotoxic to the human oral epithelial cells with low basal mTORC1/2 activation. In an effect to identify possible AZD-2014 resistance factors, we showed that the anti-apoptosis protein Bcl-2 was upregulated in AZD-2014-resistant SQ20B HNSCC cells. Inhibition of Bcl-2 by ABT-737 (a known Bcl-2 inhibitor) or Bcl-2 shRNA dramatically potentiated AZD-2014 lethality against HNSCC cells. On the other hand, exogenous overexpression of Bcl-2 largely attenuated AZD-2014’s activity against HNSCC cells. For the in vivo studies, we showed that oral gavage of AZD-2014 suppressed SQ20B xenograft growth in severe combined immunodeficient (SCID) mice. It also significantly improved mice survival. Importantly, AZD-2014’s anti-HNSCC activity in vivo was potentiated with co-administration of ABT-737. The preclinical results of this study suggest that AZD-2014 could be further tested as a valuable anti-HNSCC agent, either alone or in combination with Bcl-2 inhibitors. - Highlights: • AZD-2014 blocks mTORC1/2 activation in HNSCC cells. • AZD-2014 suppresses HNSCC cell proliferation. • AZD-2014 activates caspase-3 and apoptosis in HNSCC cells. • Bcl-2 is the key resistance factor of AZD-2014 in HNSCC cells. • ABT-737 sensitizes AZD-2014-induced anti-HNSCC activity in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a strong AHR agonist, causes significant suppression of human B cell activation and differentiation. The current studies describe the identification of Src homology phosphatase 1 (SHP-1) encoded by the gene PTPN6 as a putative regulator of TCDD-mediated suppression of B cell activation. Shp-1 was initially identified through a genome-wide analysis of AHR binding in mouse B cells in the presence of TCDD. The binding of AHR to the PTPN6 promoter was further confirmed using electrophoretic mobility shift assays in which, specific binding of AHR was detected at four putative DRE sites within PTPN6 promoter. Time-course measurements performed in human B cells highlighted a significant increase in SHP-1 mRNA and protein levels in the presence of TCDD. The changes in the protein levels of SHP-1 were also observed in a TCDD concentration-dependent manner. The increase in SHP-1 levels was also seen to occur due to a change in early signaling events in the presence of TCDD. We have shown that BCL-6 regulates B cell activation by repressing activation marker CD80 in the presence of TCDD. TCDD-treatment led to a significant increase in the double positive (SHP-1{sup hi} BCL-6{sup hi}) population. Interestingly, treatment of naïve human B cells with SHP-1 inhibitor decreased BCL-6 protein levels suggesting possible regulation of BCL-6 by SHP-1 for the first time. Collectively, these results suggest that SHP-1 is regulated by AHR in the presence of TCDD and may, in part through BCL-6, regulate TCDD-mediated suppression of human B cell activation. - Highlights: • SHP-1 encoded by the gene PTPN6 is directly activated by the AHR. • AHR binds to dioxin response elements within the SHP-1 promoter in a TCDD-inducible manner. • TCDD-mediated increase in SHP-1 levels is observed in primary human B cells. • Higher SHP-1 levels help in maintaining high BCL-6 levels in the presence of TCDD. • In the presence of SHP-1 inhibitor, decreased BCL-6 levels are observed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

First-Principles Dissociation Pathways of BCl 3 on the Si(100)-2 × 1 Surface

BCl 3 is a promising acceptor precursor for atomic-precision δ-doping of silicon, as it has been observed to rapidly dissociate into boron doped into the silicon surface and surface chlorine, which can be removed upon annealing. The chemical pathway and the resulting kinetics, through which BCl 3 adsorbs and dissociates on silicon, however, have only been partially explained. Here, in this work, we use density functional theory to expand the dissociation reactions of BCl 3 to include reactions that take place across multiple silicon dimer rows and reactions which end in a bare B atom either at the surface, substituted for a surface silicon, or in a subsurface position. We further simulate the resulting scanning tunneling microscopy images for each of these BCl x dissociation fragments, demonstrating that they often display distinct features that may allow for relatively confident experimental identification. Finally, we input the full dissociation pathway for BCl 3 into a kinetic Monte Carlo model, which simulates realistic reaction pathways as a function of environmental conditions, such as the pressure and temperature of dosing. We find that BCl 2 is broadly dominant at low temperatures, while high temperatures and ample space on the silicon surface for dissociation encourage the formation of bridging BCl fragments and B substitutions on the surface. This work provides the chemical mechanisms for understanding atomic-precision doping of Si with B, enabling a number of relevant quantum applications, such as bipolar nanoelectronics, acceptor-based qubits, and superconducting Si.

Campbell, Quinn T. [Sandia National Laboratories (↗
DOE OSTI2018

BMP4 signaling in NPCs upregulates Bcl-xL to promote their survival in the presence of FGF-2

Highlights: • BMP4 promoted survival of neural stem/progenitor cells (NPCs) in the presence of FGF-2. • BMP4 activated Smad1/5/8 signaling and promoted Id1 and Bcl-xL expression. • BMP4 inhibited cytochrome c release from mitochondria via Bcl-xL expression. We previously reported that BMP4 does not promote proliferation or differentiation of CD44-positive astrocyte precursor cells (APCs) but greatly promotes their survival in the presence of fibroblast growth factor-2 (FGF-2). In this study, we examined if BMP4 acts as a survival factor also for neural stem/progenitor cells (NPCs) isolated from ganglionic eminence of neonatal mouse brain. We found BMP4 promotes survival but not proliferation or differentiation of these cells, just as in the case for CD44-positive APCs. Microarray analysis revealed some candidate molecules in the signaling pathway downstream of BMP4. Among them, we focused on Id1 (inhibitor of DNA-binding 1) and Bcl-xL in this study. Expression of both genes was promoted in the presence of BMP4, and this promotion was reduced by dorsomorphin, an inhibitor of BMP4 signaling. Furthermore, cytochrome c release from mitochondria was significantly reduced in the presence of BMP4, suggesting up-regulation of Bcl-xL activity by BMP4. Id1 siRNA reduced the expression of Bcl-xL, and negated survival promoting effect of BMP4. These data suggest that BMP4 promotes survival of NPCs by enhancing the anti-apoptotic function of Bcl-xL via BMP4-Smad1/5/8-Id1 signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

BCL-2 proteins and apoptosis: Recent insights and unknowns

Highlights: • The pro-apoptotic BCL-2 proteins can commit cells to apoptosis. • BAX and BAK are regulated by dynamic shuttling between mitochondria and cytosol of healthy cells. • BH3-only proteins, regulators of BAX and BAK, are not required for BAX activation. • Recent super-resolution microscopy studies provide novel insights into the active BAX complex. Proteins of the B-cell lymphoma-2 (BCL-2) family control the intrinsic apoptosis pathway. The pro-apoptotic BCL-2 proteins BAX and BAK can commit a cell to its programmed death by permeabilizing the outer mitochondrial membrane (OMM) and subsequent initiation of the caspase cascade. Therefore, the activities of BAX and BAK are precisely controlled by a complex network of proteins inside and outside the BCL-2 family. Cells survive by constant control of dynamic translocation and retrotranslocation of BAX and BAK to the mitochondria and back into the cytosol. Recent insights into BAX/BAK shuttling, BCL-2 protein interactions, the role of BH3-only proteins in apoptosis signaling and the active BAX complex set the stage for the development of novel strategies in cancer therapy and the analysis of cellular predisposition to apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

BCL-2: Long and winding path from discovery to therapeutic target

In 1988, the BCL-2 protein was found to promote cancer by limiting cell death rather than enhancing proliferation. This discovery set the wheels in motion for an almost 30 year journey involving many international research teams that has recently culminated in the approval for a drug, ABT-199/venetoclax/Venclexta that targets this protein in the treatment of cancer. This review will describe the long and winding path from the discovery of this protein and understanding the fundamental process of apoptosis that BCL-2 and its numerous homologues control, through to its exploitation as a drug target that is set to have significant benefit for cancer patients. - Highlights: • BCL-2 proteins control the intrinsic or mitochondrial pathway of apoptosis. • Defective apoptosis is a hallmark of cancer. • BH3-mimetics inhibit pro-survival BCL-2 proteins to induce cancer cell death. • ABT-199/venetoclax is approved for treatment of chronic lymphocytic leukaemia.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ABT-199-mediated inhibition of Bcl-2 as a potential therapeutic strategy for nasopharyngeal carcinoma

Highlights: • ABT-199 can effectively induce nasopharyngeal carcinoma cell apoptosis free of cytotoxic agent. • ABT-199 can cause elevated Noxa expression in nasopharyngeal carcinoma. • Dual Mcl-1/Bcl-2 inhibition with ABT-199 and Mcl-1 inhibitor S63845 works synergistically and demonstrates promise for future NPC treatment. Aberrant overexpression of Bcl-2 protein has been detected in 80% of nasopharyngeal carcinoma (NPC), and Bcl-2 family proteins are implicated in both NPC oncogenesis and chemotherapy resistance. Previous studies have shown that while treatment of NPC cells with Bcl-2 family inhibitors alone is rarely effective, concomitant treatment with a cytotoxic reagent such as cisplatin can increase efficacy through a synergistic effect. The aim of the current work was to determine how we might increase the efficacy of Bcl-2 family inhibitors in the absence of cytotoxic reagents, which are associated with negative side effect profiles.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SPG6 supports development of acute myeloid leukemia by regulating BMPR2-Smad-Bcl-2/Bcl-xl signaling

Highlights: • Up-regulated expression of SPG6 correlated with poor survival of AML patients. • Knockdown expression of SPG6 suppresses growth and promotes apoptosis of AML cells. • SPG6 regulates BMPR2-Smad-Bcl-2/Bcl-xl signaling in AML cells. Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. To effectively treat AML, new molecular targets and therapeutic approaches must be identified. In silico analysis of several available databases of AML patients showed that the expression of Spastic Paraplegia 6 Protein (SPG6) significantly inversely correlates with the overall survival of AML patients. To determine whether SPG6 supports AML development, we employed an shRNA-encoding lentivirus system to inhibit SPG6 expression in human AML cells including NB4 and MV4-11 cells. Knockdown expression of SPG6 resulted in decreased cell growth and elevated apoptosis of these leukemia cells. Notably, the SPG6 deficiency resulted in higher BMPR2 expression indicating that BMPR2 signaling contributes to AML pathogenesis. Furthermore, SPG6 deficiency promoted phosphorylation of Smad1/5/9 and decreased transcription of Bcl-2 and Bcl-xl. Our study suggests that SPG6 contributes to AML pathogenesis, and suggests that inhibition of SPG6 may be novel strategy for treating human AML.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Materials Data on Ag(BCl)6 by Materials Project

Ag(BCl)6 is alpha-like structured and crystallizes in the cubic Pa-3 space group. The structure is zero-dimensional and consists of eight Ag(BCl)6 clusters. Ag is bonded in a 6-coordinate geometry to six Cl atoms. There are three shorter (2.87 Å) and three longer (2.88 Å) Ag–Cl bond lengths. There are two inequivalent B sites. In the first B site, B is bonded in a single-bond geometry to one Cl atom. The B–Cl bond length is 1.79 Å. In the second B site, B is bonded in a single-bond geometry to one Cl atom. The B–Cl bond length is 1.80 Å. There are two inequivalent Cl sites. In the first Cl site, Cl is bonded in a distorted single-bond geometry to one Ag and one B atom. In the second Cl site, Cl is bonded in a distorted water-like geometry to one Ag and one B atom.

36 MATERIALS SCIENCE↗
DOE OSTI2017

RACK1 promotes radiation resistance in esophageal cancer via regulating AKT pathway and Bcl-2 expression

RACK1 is a seven Trp-Asp 40 repeat protein, which interacts with a wide range of kinases and proteins. RACK1 plays an important role in the proliferation and progression of various cancers. The aim of this study is to detect the role of RACK1 in the radioresistance in esophageal cancer. The results indicated that downregulation of RACK1 reduced the colony formation ability, proliferation ability and resistance of cells to radiation effection through regulating the radiation-related proteins including pAKT, Bcl-2 and Bim; whereas upregulation of RACK1 promoted the ability and radioresistance of ESCC cells. Our findings suggest that RACK1 promotes proliferation and radioresistance in ESCC cells by activating the AKT pathway, upregulating Bcl-2 expression and downregulating protein levels of Bim. Our study fills in gaps in the field of RACK1 and radiation resistance and may provide new possibilities for improving strategies of radiotherapy in esophageal cancer. - Highlights: • RACK1 is proposed to influence the proliferation ability of cells after irradiation. • Present the relationship between RACK1 and radiation resistance of esophageal cancer. • Analyze the mechanism by which RACK1 plays a role in radiation resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy

Highlights: • Activation of mTOR prevents high glucose-induced apoptosis in Schwann cells. • The mTORC1 regulates high glucose-induced mitochondria-controlled apoptosis in Schwann cells. • Phosphorylation of S6K1 as mTORC1 downstream target affects high glucose-induced cell apoptosis in Schwann cells. Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques. The results showed that phospho-mTOR (Ser 2448) was decreased in the sciatic nerves of diabetic mice, concomitant with decreased Bcl-2, increased Bax, cleaved caspase-3 and cell apoptosis. In addition, high glucose treatment for 72 h caused a 35.95% decrease in the phospho-mTOR (Ser 2448)/mTOR ratio, a 65.50% decrease in the phospho-S6K1 (Thr 389)/S6K1 ratio, a 3.67-fold increase in the Bax/Bcl-2 ratio and a 1.47-fold increase in the cleaved caspase-3/caspase-3 ratio. Furthermore, mTORC1 inhibition, rather than mTORC2 inhibition, resulted in mitochondrial controlled apoptosis in RSC96 cells by silencing RAPTOR or RICTOR. Again, suppression of the mTORC1 pathway by a chemical inhibitor led to mitochondrial controlled apoptosis in cultured RSC96 cells in vitro. By contrast, activation of the mTORC1 pathway with MHY1485 prevented decreased phospho-S6K1 (Thr 389) levels caused by high glucose and cell apoptosis. Additionally, constitutive activation of S6K1 avoided high glucose-induced cell apoptosis in RSC96 cells. In summary, our findings suggest that activating mTORC1/S6K1 signaling in Schwann cells may be a promising strategy for the prevention and treatment of DPN.

60 APPLIED LIFE SCIENCES↗