Pharma Focus Asia

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

Chao Han, Guopeng Yu, Yuanshen Mao, Shangqing Song,Long Li,Lin Zhou, Zhong Wang,Yushan Liu, Minglun Li, Bin Xu.

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.

Introduction

As an androgen-dependent disease, prostate cancer (PCa) is one of the most common genitourinary tumors in men, and its incidence increases with age. In 2020, the United States is expected to have approximately 191,930 new cases and 33,330 deaths, surpassing lung cancer and becoming the most common malignant tumor in men [1]. To date, androgen deprivation therapy (ADT) is the gold standard regimen for advanced PCa patients, especially for those with metastasis [2]. While PCa progression is initially dependent on androgen, such ADT is often followed by a relapse owing to the growth of tumor cells in an androgen-independent manner [3]. This androgen-independent prostate cancer (AIPC), also known as castration-resistant prostate cancer (CRPC) is far deadlier than androgen-dependent prostate cancer (ADPC), and fewer clinical options exist for CRPC patients [4–6].

The exact mechanisms governing AIPC development are of great interest, but remain incompletely understood. We have previously reported on a key platelet activating factor (PAF) synthetase known as Lysophosphatidylcholine Acyltransferase1 (LPCAT1) that is highly expressed in CRPC tissue and cell samples, and we have shown that dihydrotestosterone (DHT) treatment induces Wnt/β-catenin-dependent PAF production and LPCAT1 expression [7].

Materials and methods

Experimental model development

In vivo overexpression experiments, 8-week-old male BALB/c nude mice (Slaccas Laboratory Inc., Shanghai, China) were used. A plasmid encoding for LPCAT1 or empty vector control was transfected into C4-2 cells. The 18 mice were randomly divided into overexpressing group (9 mice) and control group (9 mice). Following transfection, cells (overexpressing group and control) were suspended in a 50:50 mixture of PBS and Matrigel (BD, Franklin Lakes, NJ, USA), and 3 × 106 cells were subcutaneously injected into the flanks of these mice. Mice were monitored every 3 days and were sacrificed before the tumor volume reached 1000 mm3. The tumor volume of all mice was less than 1000mm3 in 6 weeks after transfection and no mice died before meeting criteria for euthanasia. In order to alleviate suffering, all mice were sacrificed by cervical spine dislocation after anesthesia by Isoflurane.

Discussion

In this study, we investigated the molecular mechanisms by which LPCAT1 contributes to the progression of CRPC. We showed that LPCAT1 drives the proliferation and invasive potential of CRPC cells both in vitro and in vivo. LPCAT1-induced increases in cell migration and invasion were associated with PAF signaling, such that PAF-AH ablated this enhanced motility upon LPCAT1 overexpression, whereas exogenous PAF restored this motility upon LPCAT1 knockdown. LPCAT1-mediated increases in cell proliferation were unrelated to PAF expression, and were instead linked to androgen-dependent LPCAT1 nuclear localization, Histone H4 O-palmitoylation, and increased synthesis of mRNA. Overexpressing LPCAT1 also made CRPC cells less sensitive to paclitaxel.

Citation: Han C, Yu G, Mao Y, Song S, Li L, Zhou L, et al. (2020) LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production. PLoS ONE 15(11): e0240801. https://doi.org/10.1371/journal.pone.0240801

Editor: Chih-Pin Chuu, National Health Research Institutes, TAIWAN

Received: May 30, 2020; Accepted: October 3, 2020; Published: November 2, 2020.

Copyright: © 2020 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The authors acknowledge funding from the National Natural Science Foundation of China, 81472398, to Dr. Bin Xu; Shanghai Rising-Star Program, 15QA1404900, to Dr. Bin Xu; Interdisciplinary research of 9th People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 201818042, to Dr. Bin Xu; and Fundamental Research Program Funding of Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, JYZZ006, to Dr. Guopeng Yu. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: LPCAT1, Lysophosphatidylcholine Acyltransferase1; CRPC, castration resistant prostate cancer; PCa, prostate cancer; ADT, Androgen deprivation therapy; AIPC, androgen-independent prostate cancer; APC, androgen-dependent prostate cancer; PAF, platelet activating factor; DHT, dihydrotestosterone; PAF-AH, PAF-acetylhydrolases; FBS, fetal bovine serum; PI, propidium iodide.

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