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LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production.

ABSTRACT: Our previously study shown that Lysophosphatidylcholine Acyltransferase1 (LPCAT1) is overexpressed in castration resistant prostate cancer (CRPC) relative to primary prostate cancer (PCa), and androgen controls its expression via the Wnt signaling pathway. While highly expressed in CRPC, the role of LPCAT1 remains unclear. In vitro cell experiments referred to cell transfection, mutagenesis, proliferation, migration, invasion, cell cycle progression and apoptosis, Western blotting, Pulse-chase RNA labeling. BALB/c nude mice were used for in vivo experiments. We found that LPCAT1 overexpression enhanced the proliferation, migration, and invasion of CRPC cells both in vitro and in vivo. Silencing of LPCAT1 reduced the proliferation and the invasive capabilities of CRPC cells. Providing exogenous PAF to LPCAT1 knockdown cells increased their invasive capabilities; however platelet activating factor acetylhydrolase (PAF-AH) and the PAFR antagonist ABT-491 both reversed this phenotype; proliferation of CRPC cells was not affected in either model. LPCAT1 was found to mediate CRPC growth via nuclear re-localization and Histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates. We also found that LPCAT1 overexpression led to CRPC cell resistance to treatment with paclitaxel. LPCAT1 overexpression in CRPC cells drives tumor progression via increased mRNA synthesis and PAF production. Our results highlight LPCAT1 as a viable therapeutic target in the context of CRPC.

SUBMITTER: Han C

PROVIDER: S-EPMC7605678 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production.

Han Chao C Yu Guopeng G Mao Yuanshen Y Song Shangqing S Li Long L Zhou Lin L Wang Zhong Z Liu Yushan Y Li Minglun M Xu Bin B

PloS one 20201102 11

Our previously study shown that Lysophosphatidylcholine Acyltransferase1 (LPCAT1) is overexpressed in castration resistant prostate cancer (CRPC) relative to primary prostate cancer (PCa), and androgen controls its expression via the Wnt signaling pathway. While highly expressed in CRPC, the role of LPCAT1 remains unclear. In vitro cell experiments referred to cell transfection, mutagenesis, proliferation, migration, invasion, cell cycle progression and apoptosis, Western blotting, Pulse-chase R ...[more]

PMID: 33137125

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Project description:BackgroundAlthough recent progress has been made in treating castration resistant prostate cancer, the interplay of signaling pathways which enable castration resistant growth is incompletely understood. A data driven, multivariate approach, was used in this study to predict prostate cancer cell survival based on the phosphorylation levels of key proteins in PC3, LNCaP, and MDA-PCa-2b cell lines in response to EGF, IGF1, IL6, TNF?, dihydrotestosterone, and docetaxel treatment.MethodsThe prostate cancer cell lines were treated with ligands or inhibitors, cell lyates were collected, and the amount of phosphoprotein quantified using 384 well ELISA assays. In separate experiments, relative cell viability was determined using an MTT assay. Normalized data was imported into Matlab where regression analysis was performed.ResultsBased on a linear model developed using partial least squares regression, p-Erk1/2 was found to correlate with castration resistant survival along with p-RPS6, and this model was determined to have a leave-one-out cross validated R2 value of 0.61. The effect of androgen on the phosphoproteome was examined, and increases in PI3K related phosphoproteins (p-Akt, p-RPS6, and p-GSK3) were observed which accounted for the majority of the significant increase in androgen-mediated cell survival. Simultaneous inhibition of the PI3K pathway and treatment with androgen resulted in a non-significant increase in survival. Given the strong effect of PI3K related signaling in enabling castration resistant survival, the specific effect of mTor versus complete inhibition was examined using targeted inhibitors. It was determine that mTor inhibition accounts for 52% of the effect of complete PI3K inhibition on cell survival. The differences in signaling between the cell lines were explored it was observed that MDA-PCa-2b exhibited far less activation of p-Erk in response to varying treatments, explaining one of the reasons for the lack of castration resistance.ConclusionIn this work, regression analysis to the phosphoproteome was used to illustrate the sources of castration resistance between the cell lines including reduced p-Erk signaling in MDA-PCa-2b and variations in p-JNK across the cell lines, as well as studying the signaling pathways which androgen acts through, and determining the response to treatment with targeted inhibitors.

Dataset Information

LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production.

Publications

LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production.

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