Silibinin induces mitochondrial NOX4-mediated endoplasmic reticulum stress response and its subsequent apoptosis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Silibinin, a milk thistle compound, exhibits chemopreventive effects and induces apoptosis in cancer cells.
• The precise mechanism of silibinin-induced apoptosis, particularly the role of reactive oxygen species (ROS) in prostate cancer, remains unclear.
• Reactive oxygen species (ROS) are implicated in various signaling pathways, but their primary source in this context is not well-defined.

Purpose of the Study:

• To investigate the effect of silibinin on prostate cancer cell growth and apoptosis.
• To elucidate the role of ROS in silibinin-induced apoptosis in prostate cancer PC-3 cells.
• To identify the specific source and signaling pathway of ROS involved in silibinin's anti-cancer effects.

Main Methods:

• MTT assay was used to assess silibinin's impact on prostate cell viability.
• Flow cytometry was employed to detect ROS production and quantify apoptosis.
• Western blotting and RT-PCR were utilized to analyze the expression of apoptosis- and ER-related proteins and genes.

Main Results:

• Silibinin treatment led to increased mitochondrial ROS production, mediated by NOX4 expression, ultimately inducing apoptosis.
• Mitochondrial ROS were found to induce endoplasmic reticulum (ER) stress by disrupting calcium (Ca2+) homeostasis.
• Inhibition of ROS, specifically by targeting NOX4, reduced silibinin-induced apoptosis, Ca2+ levels, and ER stress response.

Conclusions:

• Silibinin induces apoptosis in prostate cancer cells via a mitochondrial ROS-dependent pathway involving NOX4.
• This process is linked to the disruption of calcium homeostasis and subsequent ER stress.
• Targeting NOX4, the mitochondrial ROS producer, presents a potential therapeutic strategy for prostate cancer treatment.