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Ophiopogonin D' induces RIPK1?dependent necroptosis in androgen?dependent LNCaP prostate cancer cells.

ABSTRACT: Ophiopogonin D' (OPD') is a natural compound extracted from Ophiopogon japonicus, which is a plant used in traditional Chinese medicine. Our previous study has indicated that OPD' exhibits antitumor activity against androgen?independent prostate cancer (PCa), but the effects and the underlying molecular mechanism of action of OPD' in androgen?dependent PCa were unclear. In the present study, OPD' induced significant necroptosis in androgen?dependent LNCaP cancer cells by activating receptor?interacting serine/threonine?protein kinase 1 (RIPK1). Exposure to OPD' also increased Fas ligand (FasL)?dependent RIPK1 protein expression. The OPD'?induced necroptosis was inhibited by a RIPK1 inhibitor necrostatin?1, further supporting a role for RIPK1 in the effects of OPD´. The antitumor effects of OPD' were also inhibited by a mixed lineage kinase domain?like protein (MLKL) inhibitor necrosulfonamide. Following treatment with inhibitors of RIPK1 and MLKL, the effects of OPD' on LNCaP cells were inhibited in an additive manner. In addition, co?immunoprecipitation assays demonstrated that OPD' induced RIPK3 upregulation, leading to the assembly of a RIPK3?MLKL complex, which was independent of RIPK1. Furthermore, OPD' increased the expression of Fas?associated death domain, which is required to induce necroptosis in LNCaP cells. OPD' also regulated the expression levels of FasL, androgen receptor and prostate?specific antigen in a RIPK1?dependent manner. These results suggested that OPD' may exhibit potential as an anti?PCa agent by inducing RIPK1? and MLKL?dependent necroptosis.

SUBMITTER: Lu Z

PROVIDER: S-EPMC6959467 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Ophiopogonin D' induces RIPK1‑dependent necroptosis in androgen‑dependent LNCaP prostate cancer cells.

Lu Zongliang Z Wu Changpeng C Zhu Mingxing M Song Wei W Wang He H Wang Jiajia J Guo Jing J Li Na N Liu Jie J Li Yanwu Y Xu Hongxia H

International journal of oncology 20191217 2

Ophiopogonin D' (OPD') is a natural compound extracted from Ophiopogon japonicus, which is a plant used in traditional Chinese medicine. Our previous study has indicated that OPD' exhibits antitumor activity against androgen‑independent prostate cancer (PCa), but the effects and the underlying molecular mechanism of action of OPD' in androgen‑dependent PCa were unclear. In the present study, OPD' induced significant necroptosis in androgen‑dependent LNCaP cancer cells by activating receptor‑inte ...[more]

PMID: 31894265

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Project description:Objective: The purpose of this study was to evaluate the anticancer effects of Ophiopogonin D' (OPD', a natural product extracted from a traditional Chinese medicine (Radix Ophiopogonis) against androgen-independent prostate cancer cells and to explore the underlying molecular mechanism(s) of action. Methods: The CCK-8 assay was used to assess the viability of prostate cancer cells. The cell morphology was examined by an ultrastructural analysis via transmission electron microscopy. Cells in apoptosis (early and late stages) were detected using an Annexin V-FITC/propidium iodide kit with a FACSCaliber flow cytometer. JC-1, a cationic lipophilic probe, was employed to measure the mitochondrial membrane potential (MMP) of PC3 cells. Changes in the protein expression of RIPK1, C-RIPK1, caspase 8, cleaved-caspase 8, Bim, Bid, caspase 10, and cleaved-caspase 10 were evaluated by Western blotting. The mRNA expression of Bim was examined by quantitative real-time reverse transcription polymerase chain reaction. Z-VAD-FMK (a caspase inhibitor) and necrostatin-1 (a specific inhibitor of RIPK1) were utilized to determine whether the cell death was mediated by RIPK1 or caspases. PC3 and DU145 xenograft models in BALB/c nude mice were used to evaluate the anticancer activity of OPD' in vivo. Results: OPD' was shown to exert potent anti-tumor activity against PC3 cells. It induced apoptosis via a RIPK1-related pathway, increased the protein expression levels of RIPK1 and Bim, and decreased the levels of cleaved-RIPK1, caspase 8, cleaved-caspase 8, Bid, caspase 10, and cleaved-caspase 10. OPD' also increased the mRNA expression of Bim. The protein expression of Bim was decreased when cells were pre-treated with necrostatin-1. Treatment with OPD' inhibited the growth of PC3 and DU145 xenograft tumors in BALB/c nude mice. Conclusion: OPD' significantly inhibited the in vitro and in vivo growth of prostate cells via RIPK1, suggesting that OPD' may be developed as a potential anti-prostate cancer agent.

Dataset Information

Ophiopogonin D' induces RIPK1?dependent necroptosis in androgen?dependent LNCaP prostate cancer cells.

Publications

Ophiopogonin D' induces RIPK1‑dependent necroptosis in androgen‑dependent LNCaP prostate cancer cells.

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