# The Natural Product Secoemestrin C Inhibits Colorectal Cancer Stem Cells via p38–S100A8 Feed-Forward Regulatory Loop

## TL;DR

Secoemestrin C, a natural compound, inhibits colorectal cancer stem cells by disrupting a regulatory loop involving p38 and S100A8.

## Contribution

The study reveals a novel p38–S100A8 feedback loop mediating the anti-cancer effects of Secoemestrin C on colorectal cancer stem cells.

## Key findings

- Secoemestrin C inhibits both cancer stem cells and non-stem cells by reducing proliferation and metastasis.
- S100A8 overexpression reduces the effectiveness of Secoemestrin C, while its deficiency enhances its anti-cancer activity.
- A p38–S100A8 positive feedback loop mediates the anti-CSC effects of Secoemestrin C.

## Abstract

Cancer stem cells (CSCs) are closely associated with tumor initiation, metastasis, chemoresistance, and recurrence, which represent some of the primary obstacles to cancer treatment. Targeting CSCs has become an important therapeutic approach to cancer care. Secoemestrin C (Sec C) is a natural compound with strong anti-tumor activity and low toxicity. Here, we report that Sec C effectively inhibited colorectal CSCs and non-CSCs concurrently, mainly by inhibiting proliferation, self-renewal, metastasis, and drug resistance. Mechanistically, RNA-seq analysis showed that the pro-inflammation pathway of the IL17 axis was enriched, and its effector S100A8 was dramatically decreased in Sec C-treated cells, whose roles in the stemness of CSCs have not been fully clarified. We found that the overexpression of S100A8 hindered the anti-CSCs effect of Sec C, and S100A8 deficiency attenuated the stemness traits of CSCs to enhance the Sec C killing activity on them. Meanwhile, the p38 signal pathway, belonging to the IL17 downstream axis, can also mediate CSCs and counter with Sec C. Notably, we found that S100A8 upregulation increased the p38 protein level, and p38, in turn, promoted S100A8 expression. This indicated that p38 may have a mutual feedback loop with S100A8. Our study discovered that Sec C was a powerful anti-colorectal CSC agent, and that the positive feedback loop of p38–S100A8 mediated Sec C activity. This showed that Sec C could act as a promising clinical candidate in colorectal cancer treatment, and S100A8 could be a prospective drug target.