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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.

As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged sword, ER-phagy actively participates in various stages of development and progression in tumor cells, regulating tumorigenesis and maintaining tumor cell homeostasis. Through the unfolded protein response (UPR), the B cell lymphoma 2 (BCL-2) protein family, the Caspase signaling pathway, and others, ER-phagy plays an initiating role in tumor occurrence, migration, stemness, and proliferation. At the same time, many vital proteins strongly associated with ER-phagy, such as family with sequence similarity 134 member B (FAM134B), translocation protein SEC62 (SEC62), and C/EBP-homologous protein (CHOP), can produce a marked effect in many complex environments, which ultimately lead to entirely different tumor fates. Our article comprehensively focused on introducing the relationship and interaction between ER-phagy and cancers, as well as their molecular mechanism and regulatory pathways. Via these analyses, we tried to clarify the possibility of ER-phagy as a potential target for cancer therapy and provide ideas for further research.