# Methyl Protodioscin Promotes Ferroptosis of Prostate Cancer Cells by Facilitating Dissociation of RB1CC1 from the Detergent-Resistant Membranes and Its Nuclear Translocation

## TL;DR

Methyl protodioscin causes prostate cancer cell death through a process called ferroptosis by moving a protein called RB1CC1 to the nucleus.

## Contribution

The study reveals a novel mechanism by which methyl protodioscin induces ferroptosis via RB1CC1 nuclear translocation.

## Key findings

- MPD reduces glutathione peroxidase 4 and increases acyl-CoA synthetase long chain family member 4.
- MPD causes RB1CC1 to move from detergent-resistant membranes to the nucleus, promoting ferroptosis.
- JNK signaling is involved in RB1CC1 nuclear translocation, as SP600125 inhibits this process.

## Abstract

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscorea plants, has been shown to effectively inhibit proliferation of prostate cancer cells in vitro and in vivo. However, the mechanism underlying this inhibitory action remains unclear. To elucidate the mechanism, we used mass spectrometry to analyze protein rearrangements in detergent-resistant membranes (DRMs). Ferroptosis-related factors were identified in cells in vitro and in vivo. MPD induced the expression of acyl-CoA synthetase long chain family member 4 and reduced expression levels of glutathione peroxidase 4 and solute carrier family 7 member 11. Following MPD treatment, RB1-inducible coiled-coil 1 (RB1CC1) dissociated from DRMs and translocated from the cytoplasm to the nucleus. This translocation induced the expression of ferroptosis-related protein coiled-coil-helix-coiled-coil-helix domain containing 3, promoting ferroptosis in prostate cancer cells. As the nuclear translocation of RB1CC1 was promoted by the JNK signaling pathway, SP600125, a JNK inhibitor, prevented the MPD-induced RB1CC1 nuclear translocation. In summary, MPD induced the dissociation of RB1CC1 from DRMs and its subsequent nuclear translocation, contributing to ferroptosis of prostate cancer cells.