المؤلفون: Berg, Anastasia L, Showalter, Megan R, Kosaisawe, Nont, Hu, Michelle, Stephens, Nathanial C, Sa, Michael, Heil, Hailey, Castro, Noemi, Chen, Jenny J, VanderVorst, Kacey, Wheeler, Madelyn R, Rabow, Zachary, Cajka, Tomas, Albeck, John, Fiehn, Oliver, Carraway, Kermit L

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Women's Health, Aetiology, 2.1 Biological and endogenous factors, Animals, Mice, Humans, Female, Docosahexaenoic Acids, Breast Neoplasms, Phosphates, Reactive Oxygen Species, Lysophospholipids, Lysosomes, Breast cancer, Bis(monoacylglycerol)phosphate, BMP, Lipidomics, Lysosomal membrane permeabilization, Polyunsaturated fatty acids, Reactive oxygen species, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/9wr544pf
https://escholarship.org/content/qt9wr544pf/qt9wr544pf.pdf

المؤلفون: Berg, Anastasia L, Rowson-Hodel, Ashley, Hu, Michelle, Keeling, Michael, Wu, Hao, VanderVorst, Kacey, Chen, Jenny J, Hatakeyama, Jason, Jilek, Joseph, Dreyer, Courtney A, Wheeler, Madelyn R, Yu, Ai-Ming, Li, Yuanpei, Carraway, Kermit L

المصدر: Cancers. 14(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Stem Cell Research - Nonembryonic - Human, Digestive Diseases, Breast Cancer, Orphan Drug, Cancer, Rare Diseases, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, breast cancer, cancer stem cell, therapy resistance, cationic amphiphilic drug, lysosome-dependent cell death, Oncology and carcinogenesis

الوصف: The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/6354g7jr

المؤلفون: Krois, Charles R, Vuckovic, Marta G, Huang, Priscilla, Zaversnik, Claire, Liu, Conan S, Gibson, Candice E, Wheeler, Madelyn R, Obrochta, Kristin M, Min, Jin H, Herber, Candice B, Thompson, Airlia C, Shah, Ishan D, Gordon, Sean P, Hellerstein, Marc K, Napoli, Joseph L

المصدر: Cellular and Molecular Life Sciences. 76(12)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Obesity, Diabetes, Nutrition, Underpinning research, 1.1 Normal biological development and functioning, Metabolic and endocrine, Oral and gastrointestinal, Adipose Tissue, Brown, Adiposity, Animals, Diet, Fat-Restricted, Eating, Energy Metabolism, Fasting, Female, Gene Deletion, Glucose Intolerance, Hydroxysteroid Dehydrogenases, Insulin Resistance, Lipid Metabolism, Male, Mice, Inbred C57BL, Thermogenesis, Tretinoin, Vitamin A, Adipose, Lipid metabolism, Mitochondria membrane potential, Retinol dehydrogenase, Retinoic acid, Retinol, Physiology, Clinical Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Oncology and carcinogenesis

الوصف: RDH1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here, we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. Glucose intolerance and insulin resistance develop following increased adiposity. Despite the increase in white fat pads, epididymal white adipose does not express Rdh1, nor does muscle. Brown adipose tissue (BAT) and liver express Rdh1 at relatively high levels compared to other tissues. Rdh1 ablation lowered body temperatures during ambient conditions. Given the decreased body temperature, we focused on BAT. A lack of differences in BAT adipogenic gene expression between Rdh1-null mice and wild-type mice, including Pparg, Prdm16, Zfp516 and Zfp521, indicated that the phenotype was not driven by brown adipose hyperplasia. Rather, Rdh1 ablation eliminated the increase in BAT atRA that occurs after re-feeding. This disruption of atRA homeostasis increased fatty acid uptake, but attenuated lipolysis in primary brown adipocytes, resulting in increased lipid content and larger lipid droplets. Rdh1 ablation also decreased mitochondrial proteins, including CYCS and UCP1, the mitochondria oxygen consumption rate, and disrupted the mitochondria membrane potential, further reflecting impaired BAT function, resulting in both BAT and white adipose hypertrophy. RNAseq revealed dysregulation of 424 BAT genes in null mice, which segregated predominantly into differences after fasting vs after re-feeding. Exceptions were Rbp4 and Gbp2b, which increased during both dietary conditions. Rbp4 encodes the serum retinol-binding protein-an insulin desensitizer. Gbp2b encodes a GTPase. Because Gbp2b increased several hundred-fold, we overexpressed it in brown adipocytes. This caused a shift to larger lipid droplets, suggesting that GBP2b affects signaling downstream of the β-adrenergic receptor during basal thermogenesis. Thus, Rdh1-generated atRA in BAT regulates multiple genes that promote BAT adaptation to whole-body energy status, such as fasting and re-feeding. These gene expression changes promote optimum mitochondria function and thermogenesis, limiting adiposity. Attenuation of adiposity and insulin resistance suggests that RDH1 mitigates metabolic syndrome.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/3t97n394