Scaffold attachment factor B1 (SAFB1) heterozygosity does not influence Wnt-1 or DMBA-induced tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Scaffold Attachment Factor B1 (SAFB1) is a multifunctional protein which has been implicated in breast cancer previously. We recently generated SAFB1 knockout mice (SAFB1^-/-), but pleiotropic phenotypes including high lethality, dwarfism associated with low IGF-I levels, and infertility and subfertility in male and female mice, respectively, do not allow for straightforward tumorigenesis studies in these mice. Therefore, we asked whether SAFB1 heterozygosity would influence tumor development and progression in MMTV-Wnt-1 oncomice or DMBA induced tumorigenicity, in a manner consistent with haploinsufficiency of the remaining allele.</p> <p>Methods</p> <p>We crossed female SAFB1^+/-(C57B6/129) mice with male MMTV-Wnt-1 (C57B6/SJL) mice to obtain SAFB1^+/+/Wnt-1, SAFB1^+/-/Wnt-1, and SAFB1^+/-mice. For the chemical induced tumorigenesis study we treated 8 weeks old SAFB1^+/-and SAFB^+/+BALB/c mice with 1 mg DMBA once per week for 6 weeks. Animals were monitored for tumor incidence and tumor growth. Tumors were characterized by performing H&E, and by staining for markers of proliferation and apoptosis.</p> <p>Results</p> <p>We did not detect significant differences in tumor incidence and growth between SAFB1^+/+/Wnt-1 and SAFB1^+/-/Wnt-1 mice, and between DMBA-treated SAFB1^+/+and SAFB1^+/-mice. Histological evaluation of tumors showed that SAFB1 heterozygosity did not lead to changes in proliferation or apoptosis. There were, however, significant differences in the distribution of tumor histologies with an increase in papillary and cribriform tumors, and a decrease in squamous tumors in the SAFB1^+/-/Wnt-1 compared to the SAFB1^+/+/Wnt-1 tumors. Of note, DMBA treatment resulted in shortened survival of SAFB1^+/-mice compared to their wildtype littermates, however this trend did not reach statistical significance.</p> <p>Conclusion</p> <p>Our data show that SAFB1 heterozygosity does not influence Wnt-1 or DMBA-induced mammary tumorigenesis.</p

Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies

Eu3+ doped alpha-sodium gadolinium fluoride luminomagnetic nanophosphor as a bimodal nanoprobe for high-contrast in vitro bioimaging and external magnetic field tracking applications

Herein, we introduce a novel strategy for the synthesis of Eu3+ doped alpha-sodium gadolinium fluoride (alpha-NaGd0.88F4:Eu0.12(3+)) based luminomagnetic nanophosphors using a hydrothermal route. The synthesized nanophosphor has exceptional luminescent and paramagnetic properties in a single host lattice, which is highly desirable for biomedical applications. This highly luminescent nanophosphor with an average particle size similar to 5 +/- 3 nm enables high-contrast fluorescent imaging with decreased light scattering. In vitro cellular uptake is shown by fluorescent microscopy that envisages the characteristic hypersensitive red emission of Eu3+ doped alpha-sodium gadolinium fluoride centered at 608 nm (D-5(0)-F-7(2)) upon 465 nm excitation wavelength. No apparent cytotoxicity is observed. Furthermore, time-resolved emission spectroscopy and SQUID magnetic measurements successfully demonstrate a photoluminescence decay time of microseconds and an enhanced paramagnetic behavior, which holds promise for the application of nanophosphors in biomedical studies. Hence, the obtained results strongly suggest that this nanophosphor could be potentially used as a bimodal nanoprobe for high-contrast in vitro bioimaging of HeLa cells and external magnetic field tracking applications of luminomagnetic nanophosphors using permanent magnet

Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States

Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective

Probing Highly Luminescent Europium-Doped Lanthanum Orthophosphate Nanorods for Strategic Applications

Herein we have established a strategy for the synthesis of highly luminescent and biocompatible europium-doped lanthanum orthophosphate (La0.85PO4Eu0.153+) nanorods. The structure and morphogenesis of these nanorods have been probed by XRD, SEM, and TEM/HRTEM techniques. The XRD result confirms that the as-synthesized nanorods form in a monazite phase with a monoclinic crystal structure. Furthermore, the surface morphology shows that the synthesized nanorods have an average diameter of similar to 90 nm and length of similar to 2 mu m. The HRTEM images show clear lattice fringes that support the presence of better crystal quality and enhanced photoluminescence hypersensitive red emission at 610 nm (D-5(0)-F-7(2)) upon 394 nm wavelength excitation. Furthermore, time-resolved spectroscopy and an MTT assay of these luminescent nanorods demonstrate a photoluminescent decay time of milliseconds with nontoxic behavior. Hence, these obtained results suggest that the as-synthesized luminescent nanorods could be potentially used in invisible security ink and high-contrast bioimaging applications

Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways.

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis, respectively, with the activities of three major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa

ΔPSap4#5 surface-functionalized abiraterone-loaded nanoparticle successfully inhibits carcinogen-induced prostate cancer in mice: a mechanistic investigation

Abstract Prostate cancer (PCa) is one of the fatal illnesses among males globally. PCa-treatment does not include radiotherapy. Chemotherapy eventually causes drug resistance, disease recurrence, metastatic advancement, multi-organ failure, and death. Preclinical data on PCa-induced by carcinogens are truly scarce. Although some data on xenograft-PCa in animals are available, they mostly belonged to immuno-compromised animals. Here, we developed ΔPSap4#5 aptamer surface-functionalized abiraterone-loaded biodegradable nanoparticle (Apt-ABR-NP) to investigate its targeting ability to prostate-specific membrane antigen (PSMA) in carcinogen-induced PCa mice and the therapeutic efficacy of the formulation. Aptamers are called synthetic monoclonal antibodies for their target specificity. However, they are devoid of the toxicity problem generally associated with the antibody. Abiraterone is a testosterone and androgen inhibitor, a new drug molecule that shows good therapeutic efficacy in PCa. The developed nanoparticles were physicochemically characterized and used for various in vitro and in vivo investigations. Nanoparticles had an average size of 149 nm with sustained drug release that followed Korsmeyer–Peppas kinetics. In vitro investigation showed that Apt-ABR-NP produced 87.4% apoptotic cells and 95.3% loss of mitochondrial membrane potential in LNCaP cells after 48 h of incubation. In vivo gamma scintigraphy, live imaging, and biodistribution studies in prostate cancer animal models showed the predominant targeting potential of Apt-ABR-NP. Histopathological investigation showed the remarkable therapeutic efficacy of the formulation. The pharmacokinetic study showed an increased biological half-life and enhanced blood residence time of Apt-ABR-NP. Apt-ABR-NP therapy can thus minimize off-target cytotoxicity, reduce drug loss due to site-specific delivery, and deliver abiraterone in a sustained manner to the organ of interest. Thus, the present study brings new hope for better therapeutic management of PCa in the near future. Graphical Abstrac

Bifunctional Luminomagnetic Rare-Earth Nanorods for High-Contrast Bioimaging Nanoprobes

Nanoparticles exhibiting both magnetic and luminescent properties are need of the hour for many biological applications. A single compound exhibiting this combination of properties is uncommon. Herein, we report a strategy to synthesize a bifunctional luminomagnetic Gd2-xEuxO3 (x = 0.05 to 0.5) nanorod, with a diameter of similar to 20 nm and length in similar to 0.6 mu m, using hydrothermal method. Gd2O3:Eu3+ nanorods have been characterized by studying its structural, optical and magnetic properties. The advantage offered by photoluminescent imaging with Gd2O3:Eu3+ nanorods is that this ultrafine nanorod material exhibits hypersensitive intense red emission (610 nm) with good brightness (quantum yield more than 90%), which is an essential parameter for high-contrast bioimaging, especially for overcoming auto fluorescent background. The utility of luminomagnetic nanorods for biological applications in high-contrast cell imaging capability and cell toxicity to image two human breast cancer cell lines T47D and MDA-MB-231 are also evaluated. Additionally, to understand the significance of shape of the nanostructure, the photoluminescence and paramagnetic characteristic of Gd2O3:Eu3+ nanorods were compared with the spherical nanoparticles of Gd2O3:Eu3+