title: Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.
abstract: Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Ippolito
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Brandenburg
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Ge
authors.affiliation: Biomedical Mass Spectrometry Resource, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Crowley
authors.affiliation: Biomedical Mass Spectrometry Resource, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kristopher M
authors.initials: KM
authors.lastname: Kirmess
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Avik
authors.initials: A
authors.lastname: Som
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America.
authors.forename: D Andre
authors.initials: DA
authors.lastname: D'Avignon
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
authors.affiliation: Biomedical Mass Spectrometry Resource, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000143:Acids / Q000378:metabolism*; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009534:Niclosamide / Q000008:administration & dosage; D010085:Oxidative Phosphorylation / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000143:Acids; D009534:Niclosamide; D005947:Glucose