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

Abstract

AIM:

The aim of this study was to explore the antitumor effect of citrate on prostate cancer and its underlying mechanism.

MAIN 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.

KEY FINDINGS:

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.

SIGNIFICANCE:

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.

• Authors: Xirui Fan, Jinyi Zhou, Xintong Yan, Xiaowen Bi, Juanjuan Liang, Shuai Lu, Lan Luo, Da Zhou, Zhimin Yin
• Journal: Life sciences (Life Sci) Vol. 275 Pg. 119355 (Jun 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33744326 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Citric Acid
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Autophagic Cell Death (drug effects)
• Blotting, Western
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cell Line, Tumor
• Citric Acid (pharmacokinetics)
• Down-Regulation
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• PC-3 Cells
• Prostatic Neoplasms (drug therapy, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)