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Methiothepin mesylate causes apoptosis of human prostate cancer cells by mediating oxidative stress and mitochondrial

Changwon Yang¹, Gwonhwa Song¹, Whasun Lim²

¹Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.

Free Radical Biology & Medicine

|February 9, 2020

Abstract:

Prostate cancer is difficult to treat if it metastasizes to other organs. The development of prostate cancer independent of androgen is closely related to the action of neuroendocrine products. Serotonin promotes cell growth in various cancers, and antagonists for serotonin receptors are known to inhibit proliferation and induce cell death in various carcinomas. However, little is known about how antagonists for serotonin receptor function in prostate cancer. We verified apoptotic cell death in prostate cancer cell lines after treatment with methiothepin mesylate (MET), an antagonist for serotonin receptor 5-HT₁. MET induced hydrogen peroxide (H₂O₂) production and mitochondrial Ca²⁺ overload. Moreover, MET induced changes in the expression of proteins associated with endoplasmic reticulum stress, autophagy, and mitochondrial membrane potential. MET also promoted phosphorylation of JNK, which induced cell death mediated by oxidant production, as evidenced by the JNK inhibitor and oxidant scavenger. Finally, MET has the potential to prevent metastasis by inhibiting the migration of prostate cancer cells. Thus, we show that MET is a potentially novel anticancer agent that can suppress the development of prostate cancer caused by neuroendocrine differentiation.

Insights

Methiothepin mesylate (MET), a serotonin receptor antagonist, induces prostate cancer cell death and inhibits migration. This novel agent shows potential for treating neuroendocrine prostate cancer by targeting serotonin pathways.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Metastatic prostate cancer is challenging to treat, often linked to neuroendocrine product actions.
Serotonin receptor antagonists inhibit cancer cell proliferation, but their role in prostate cancer is unclear.

Purpose of the Study:

To investigate the effects of methiothepin mesylate (MET), a serotonin receptor 5-HT1 antagonist, on prostate cancer cell lines.
To explore MET's potential as a novel therapeutic agent for neuroendocrine prostate cancer.

Main Methods:

Treatment of prostate cancer cell lines with methiothepin mesylate (MET).
Analysis of apoptosis, hydrogen peroxide (H2O2) production, mitochondrial Ca2+ overload, endoplasmic reticulum stress, autophagy, and JNK phosphorylation.
Assessment of prostate cancer cell migration.

Main Results:

MET induced apoptotic cell death, H2O2 production, and mitochondrial Ca2+ overload.
MET altered protein expression related to endoplasmic reticulum stress, autophagy, and mitochondrial membrane potential.
MET promoted JNK phosphorylation, leading to oxidant-mediated cell death and inhibited cancer cell migration.

Conclusions:

Methiothepin mesylate (MET) demonstrates potential as a novel anticancer agent for prostate cancer.
MET may suppress neuroendocrine prostate cancer development by inducing cell death and inhibiting metastasis.

Read full analysis

Keywords:

Apoptosis Methiothepin mesylate Mitochondria Oxidative stress Prostate cancer

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