Targeting cancer stress-associated hyperinsulinemia and abnormal behavior mitigates lung carcinoma in postmenopausal mouse: Intervention function of peimine

Abstract

Obesity stress and its associated metabolic disruption increase the likelihood and advancement of several forms of malignancies, such as postmenopausal lung cancer in humans. Also, the mechanism of lung cancer stress-related cognitive impairment and rhythm change are still unknown. Peimine (PE), an alkaloid derived from the Fritillaria genus, has the ability to mitigate the metabolic dysfunctions induced by obesity and inhibit tumor growth. The objective of this study was to investigate the regulatory impact of PE on obese mice with postmenopausal lung cancer generated by a high fat diet. Our initial findings indicate that PE can significantly reduce the metabolic dysfunction caused by a high-fat diet in mice. This is demonstrated by better glucose tolerance and insulin resistance, reduced accumulation of lipids in the liver, and improved histological alterations in the mammary fat pad. Subsequently, the treatment of PE suppressed the formation of lung tumors caused by a high-fat diet in mice models placed in their original location. In addition, PE effectively inhibited the formation of pre-existing lung tumors in a mouse model of postmenopausal women who were fed a high-fat diet. This treatment also reduced the severity of metabolic problems. Notably, laboratory studies demonstrated that insulin exposure increased the growth and movement of lung cancer cells, but this effect was significantly reduced when the cells were co-cultured with PE. Meanwhile, PE intervention can significantly alleviate cancer stress-related cognitive impairment and disturbed circadian rhythm changes and associated gene expression abnormalities in model animals. Analysis using bioinformatics and molecular biology techniques revealed that PE has the ability to decrease the expression levels of signal transducer and activator of transcription 3 (STAT3) in the liver, mammary fat pad, and tumor tissues of postmenopausal mice with obesity generated by a high-fat diet. The inhibitory effects of PE on the growth and movement of lung cancer cells induced by insulin were completely eliminated when STAT3 expression was removed. This suggests that the suppression of STAT3 expression is crucial for PE to exert its anti-cancer effects against lung cancer in the presence of high insulin levels. The findings of our study indicate that consuming PE is highly effective in preventing and treating lung cancer that is connected with obesity. This is achieved via regulating the signaling pathway of STAT3.