Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability

Jinzhu Zhao; Leilei Li; Zhijia Wang; Linlin Li; Mingjing He; Shuhua Han; Yalong Dong; Xiaojie Liu; Wen Zhao; Yu Ke; Cong Wang

doi:10.1016/j.phrs.2021.105939

Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability

Pharmacol Res. 2021 Dec:174:105939. doi: 10.1016/j.phrs.2021.105939. Epub 2021 Oct 14.

Authors

Jinzhu Zhao¹, Leilei Li¹, Zhijia Wang¹, Linlin Li¹, Mingjing He¹, Shuhua Han¹, Yalong Dong¹, Xiaojie Liu¹, Wen Zhao¹, Yu Ke¹, Cong Wang²

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China.
² School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China. Electronic address: wangcong@zzu.edu.cn.

PMID: 34655772
DOI: 10.1016/j.phrs.2021.105939

Abstract

Cancer drug resistance is a formidable obstacle that enhances cancer stem-like cell properties, tumour metastasis and relapse. Luteolin (Lut) is a natural flavonoid with strong antitumor effects. However, the underlying mechanism(s) by which Lut protects against paclitaxel-resistant (PTX-resistant) cancer cell remains unknown. Herein, we found that Lut significantly attenuated the stem-like properties of PTX-resistant cancer cells by downregulating the expression of SOX2 protein. Additionally, further study showed that Lut could inhibit the PI3K/AKT pathway to decrease the phosphorylation level of AKT(S473) and UBR5 expression, which is an ubiquitin E3 ligase that promotes SOX2 degradation. In addition, Lut also inhibited PTX-resistant cancer cell migration and invasion by blocking epithelial-mesenchymal transition (EMT). Importantly, Lut inhibited the tumorigenic ability of oesophageal PTX-resistant cancer cells and showed no obvious toxicity in vivo. Thus, Lut has potential as a promising agent for drug-resistant oesophageal cancer therapy.

Keywords: Cancer stemness; Epithelial-mesenchymal transition; Luteolin; Oesophageal drug-resistant cancer; SOX2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Esophageal Neoplasms / drug therapy*
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism
Esophageal Neoplasms / pathology
Female
Humans
Luteolin / pharmacology
Luteolin / therapeutic use*
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplastic Stem Cells / drug effects
Paclitaxel / pharmacology
Paclitaxel / therapeutic use
Phosphatidylinositol 3-Kinases / metabolism
Protein Stability / drug effects
Proto-Oncogene Proteins c-akt / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism

Substances

Antineoplastic Agents
SOX2 protein, human
SOXB1 Transcription Factors
Proto-Oncogene Proteins c-akt
Luteolin
Paclitaxel