82 research outputs found
Fueling survival: Adipocyte-mediated modulation of iron metabolism and oxidative stress pathways in bone metastatic prostate cancer
Fueling survival: Adipocyte-mediated modulation of iron metabolism and oxidative stress pathways in bone metastatic prostate cancer
Authors: Shrila Rajendran1*, Alexis Wilson1,2, Shane Mecca1, Mackenzie Herroon1, Laimar Garmo1, and Izabela Podgorski1,2
Department of Pharmacology, Wayne State University School of Medicine1 and Cancer Biology Graduate Program, Wayne State University School of Medicine and Karmanos Cancer Institute2
Prostate cancer (PCa) commonly metastasizes to the bone marrow, where cancer cells interact with a variety of cell types that compose the bone tumor microenvironment. The interaction of interest for this research is between metastatic PCa cells and adipocytes, a major cell type in bone marrow. Numbers of marrow adipocytes increase with age, obesity and metabolic pathologies, and their impact on tumors that grow in bone is being increasingly recognized. The PCa cells in bone marrow have increased survivability and chemoresistance that may be related to their communication with bone marrow adipocytes. One mechanism of interest is the balance of lipid peroxides and iron stores within PCa during adipocyte exposure. The aim of this research is to test the hypothesis that bone marrow adipocytes support PCa survival in the bone tumor microenvironment through the modulation of iron stores and lipid peroxides. Our analysis of single-cell RNAseq data from patients with PCa bone metastases demonstrated changes in genes related to the regulation of iron and lipid peroxides, suggesting their possible role in PCa survival. Specifically, high expression of ferritin (FTH1), an iron storage protein, and low levels of nuclear receptor coactivator 4 (NCOA4), a ferritin degradation protein, were observed in tumor clusters, along with high expression of glutathione peroxidase 4 (GPX4), an enzyme that protects cells from lipid peroxides. Interestingly, when PCa cells were exposed to bone marrow-derived adipocytes in vitro, similar patterns of expression were observed (i.e., increased levels of FTH1 and GPX4, but reduced levels of NCOA4), indicating the potential role of marrow adipocytes in the regulation of iron storage and ferritin turnover. IHC staining of tumor sections from mice fed either high fat (HFD) or low fat (LFD) diet showed increased FTH1 expression in tumors from HFD mice. Notably, particularly high FTH1 presence was observed in the areas rich in adipocytes, demonstrating a potential relationship between the iron storage protein and lipids. In addition, tumor areas with augmented FTH1 showed increased expression of heme oxygenase 1 (HO-1), an antioxidant enzyme responsible for the breakdown of heme into iron and biliverdin. This was in line with our in vitro results showing an increase in HO-1 levels with adipocyte exposure, and a high FTH1 expression in cells stably overexpressing HO-1. One notable observation is that PCa cells exposed to adipocytes in Transwell co-culture in vitro, showed initially increased lipid peroxidation levels, which declined upon prolonged interaction with adipocytes. This suggests an adaptive mechanism present in PCa cells, potentially involving modulation of iron stores and HO-1 and GPX4 activity. Upon treatment with iron citrate, FTH1 protein levels increased while GPX4 protein levels decreased particularly in PCa cells cultured with adipocytes, indicating a potentially more direct relationship between FTH1 levels and GPX4 activity. To further explore this relationship, PCa cells were cultured alone or exposed to adipocytes in the presence or absence of GPX4 inhibitor, RSL3. Inhibition of GPX4 led to an increase in FTH1 and HO-1 protein levels in PCa cells, suggesting their possible roles in reducing oxidative stress from lipid peroxides during adipocyte exposure. Collectively, our data indicate that the modulation of iron storage and lipid peroxides in PCa cells by bone marrow adipocytes may play a role in the survival of metastatic PCa within the harsh bone marrow microenvironment
Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain. Introduction: The mounting evidence that osteoclasts play an important role in osteoarthritis (OA) pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain. Methods: Effects of preventative (30 and 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw withdrawal thresholds, cartilage and bone pathology, synovial inflammation, and drug exposure were studied in the monosodium iodoacetate rat model of OA pain. Results: Preventative L-006235 inhibited weight-bearing asymmetry from day 14, with this measure nearly abolished by the higher dose. In the same treatment setting, L-006235 prevented lowering of hind paw withdrawal thresholds from day 7. Exposure to L-006235 in plasma was higher for the 100 mg/kg dose, compared with 30 mg/kg. Therapeutic dosing with L-006235 from day 14 significantly inhibited weight-bearing asymmetry, compared with monosodium iodoacetate vehicle rats. Regression analysis revealed a significant interaction coefficient of the effects of L-006235 on weight-bearing asymmetry and synovitis score, but not for cartilage damage nor osteophyte scores. Conclusion: Our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides new evidence for the therapeutic potential of this target
Bone marrow adipose tissue and cancer
Interactions within the tumor-bone microenvironment are integral to both tumor growth and survival, and to development of the associated bone disease. Whereas the contribution of cells such as osteoclasts and osteoblasts to these processes are well defined, the role of bone marrow adipose tissue is less clear. Bone marrow adipocytes are highly specialized cells whose functional significance has only recently been recognized, with metabolic and endocrine functions that may facilitate tumor progression within the bone microenvironment. Understanding how bone marrow adipocytes contribute to the metastatic niche in multiple myeloma and solid tumors that metastasize to bone will ultimately reveal new therapeutic approaches
Prostate Cancer-Specific Lysine 53 Acetylation of Cytochrome <i>c</i> Drives Metabolic Reprogramming and Protects from Apoptosis in Intact Cells
Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H2O2 or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis
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