Citrate activates autophagic death of prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway. 2021

Xirui Fan, and Jinyi Zhou, and Xintong Yan, and Xiaowen Bi, and Juanjuan Liang, and Shuai Lu, and Lan Luo, and Da Zhou, and Zhimin Yin
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.

OBJECTIVE The aim of this study was to explore the antitumor effect of citrate on prostate cancer and its underlying mechanism. METHODS CCK-8 and Colony formation assay were performed to detect the anti-proliferative effect of citrate on prostate cancer. Flow cytometry analysis was conducted to investigate the pro-apoptosis effect of citrate on prostate cancer. Immunofluorescence assay was taken to detect whether citrate induced autophagy in prostate cancer. Western blot and Immunohistochemical assay were performed to explore the underlying mechanism by which citrate activates autophagic death in prostate cancer cells. Xenograft tumorigenicity assay was conducted to explore whether citrate suppressed the growth of xenograft prostate tumors in vivo. RESULTS We found citrate could significantly induce apoptosis and autophagy of prostate cancer cells in vitro and in vivo. Furthermore, treatment with autophagy inhibitor (chloroquine) drastically suppresses the apoptosis rate of prostate cancer induced by citrate. Based on the Ca2+-chelating property of citrate, the further study suggested that citrate activates autophagic cell death in prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway. Finally, citrate suppresses the growth of xenograft prostate tumors without remarkable toxicity in mice. CONCLUSIONS Our study elucidated a novel molecular mechanism about the anti-cancer activities of citrate. That citrate activates autophagic cell death of prostate cancer via downregulation CaMKII/AKT/mTOR pathway and without remarkable toxicity in mice. This study suggests that citrate might be a promising therapeutic agent for the treatment of prostate cancer.

UI MeSH Term Description Entries
D008297 Male Males
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D009368 Neoplasm Transplantation Experimental transplantation of neoplasms in laboratory animals for research purposes. Transplantation, Neoplasm,Neoplasm Transplantations,Transplantations, Neoplasm
D011471 Prostatic Neoplasms Tumors or cancer of the PROSTATE. Cancer of Prostate,Prostate Cancer,Cancer of the Prostate,Neoplasms, Prostate,Neoplasms, Prostatic,Prostate Neoplasms,Prostatic Cancer,Cancer, Prostate,Cancer, Prostatic,Cancers, Prostate,Cancers, Prostatic,Neoplasm, Prostate,Neoplasm, Prostatic,Prostate Cancers,Prostate Neoplasm,Prostatic Cancers,Prostatic Neoplasm
D005434 Flow Cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. Cytofluorometry, Flow,Cytometry, Flow,Flow Microfluorimetry,Fluorescence-Activated Cell Sorting,Microfluorometry, Flow,Cell Sorting, Fluorescence-Activated,Cell Sortings, Fluorescence-Activated,Cytofluorometries, Flow,Cytometries, Flow,Flow Cytofluorometries,Flow Cytofluorometry,Flow Cytometries,Flow Microfluorometries,Flow Microfluorometry,Fluorescence Activated Cell Sorting,Fluorescence-Activated Cell Sortings,Microfluorimetry, Flow,Microfluorometries, Flow,Sorting, Fluorescence-Activated Cell,Sortings, Fluorescence-Activated Cell
D005455 Fluorescent Antibody Technique Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy. Antinuclear Antibody Test, Fluorescent,Coon's Technique,Fluorescent Antinuclear Antibody Test,Fluorescent Protein Tracing,Immunofluorescence Technique,Coon's Technic,Fluorescent Antibody Technic,Immunofluorescence,Immunofluorescence Technic,Antibody Technic, Fluorescent,Antibody Technics, Fluorescent,Antibody Technique, Fluorescent,Antibody Techniques, Fluorescent,Coon Technic,Coon Technique,Coons Technic,Coons Technique,Fluorescent Antibody Technics,Fluorescent Antibody Techniques,Fluorescent Protein Tracings,Immunofluorescence Technics,Immunofluorescence Techniques,Protein Tracing, Fluorescent,Protein Tracings, Fluorescent,Technic, Coon's,Technic, Fluorescent Antibody,Technic, Immunofluorescence,Technics, Fluorescent Antibody,Technics, Immunofluorescence,Technique, Coon's,Technique, Fluorescent Antibody,Technique, Immunofluorescence,Techniques, Fluorescent Antibody,Techniques, Immunofluorescence,Tracing, Fluorescent Protein,Tracings, Fluorescent Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000078722 PC-3 Cells An epithelial cell line initiated from a human bone metastasis of a grade IV prostatic ADENOCARCINOMA. Human Prostatic Carcinoma Cell Line PC3,PC-3 (Human Prostatic Carcinoma) Cell Line,PC-3 Cell Line,PC3 Cell Line,PC3 Cells,Cell Line, PC-3,Cell Line, PC3,Cells, PC-3,Cells, PC3,Line, PC-3 Cell,PC 3 Cell Line,PC 3 Cells,PC-3 Cell
D000080549 Autophagic Cell Death A major activation of the autophagic pathway, characterized by massive accumulation of AUTOPHAGOSOMES and CELL DEATH. Autophagy-Dependent Cell Death,Autophagic Programmed Cell Death,Programmed Cell Death, Type II,Autophagic Cell Deaths,Autophagy Dependent Cell Death,Autophagy-Dependent Cell Deaths,Cell Death, Autophagic,Cell Death, Autophagy-Dependent,Cell Deaths, Autophagic,Cell Deaths, Autophagy-Dependent,Death, Autophagic Cell,Death, Autophagy-Dependent Cell,Deaths, Autophagic Cell,Deaths, Autophagy-Dependent Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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