Prostate cancer (PCa) is one of the common malignancies in men, ranking second in morbidity and fifth in mortality. Despite advances in screening and diagnosis, the incidence of PCa continues to increase by years1. The occurrence and development of PCa is a very complicated process, and there are many possibilities in the pathogenesis. Genetic and epigenetic changes of multiple genes, including fusion of TMPRSS2 with ERG2, amplification or overexpression of Myc3,4, deletion or inactivation of PTEN and TP535,6, mutation or amplification of the androgen receptor (AR), initiate and promote the occurrence of PCa7–9. Inflammation, oxidative stress, abnormal telomerase activity and shortening of telomere length, cell senescence and abnormal expression of non-coding RNA all promote the process of PCa10,11. PCa is highly treatable in its early stages. The treatment of localized PCa includes active surveillance, local radiotherapy and prostatectomy12. Androgen deprivation therapy (ADT) by surgical or chemical castration is the most commonly used and effective treatment for PCa patients. Unfortunately, PCa patients often develop resistance to ADT, and cancer cells will undergo genetic changes and metastasize to distant tissues and organs, developing into castration-resistant prostate cancer (CRPC)13. The 5-year survival rate of PCa patients diagnosed with local lesions as high as 99%, but it’s only 30% for patients with metastatic PCa14. The complex pathogenesis and the sharp decline in survival rate make it urgent to find new strategies or targets for the prevention and treatment of PCa.
Dysregulation of phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT) is closely associated with the development and progression of human cancer. Previous researches have shown that the activation of PI3K/AKT signaling pathway and alterations of oncogenic components in the PI3K/AKT signaling pathway can promote tumorigenesis by regulating cell migration, proliferation, survival and angiogenesis15,16. In addition, many studies have indicated that the PI3K/AKT signaling pathway is associated with the development of PCa. PI3K/AKT signaling pathway is regulated by the ErbB, EGFR and HER families to promote PCa cell growth. Inflammatory factors (CCR9, IL-6 and TLR3) can modulate the PCa cell apoptosis via PI3K/AKT signaling. The PTEN/PI3K/AKT pathway and PI3K/AKT/mTOR signaling pathway can accommodate PCa cell metastasis and invasion17. Moreover, PTEN deletion activates the PI3K/AKT/mTOR pathway, which is the most common molecular mechanism of CRPC and one of the causes of ADT resistance18. Fibroblast growth factor receptor 2 (FGFR2), has often happened somatic hotspot mutations, structural amplification and fusion in multiple cancers19. A previous study found that the loss of FGFR2 is related to the malignant progression of prostate cancer and it will be a clinical therapeutic target20.
Chemotherapy can obviously improve the prognosis and survival of PCa patients, but the adverse reactions are serious and prone to drug resistance21. Therefore, it is urgent to find new anti-tumor drugs to maintain the life of PCa patients. Scientific studies have shown that many natural products and extracts could be used as the potential anti-tumor agents of PCa in recent years22. Taraxasterol (TAX), (3β, 18α, 18α)-Urs-20(30)-en-3-ol, is a pentacyclic-triterpene compound with various biological activities. TAX can be extracted from many types of plants and is one of the main active components of Taraxacum officinale F. H. Wigg23. Previous studies have proved that TAX has anti-inflammatory, anti-oxidative and anti-carcinogenic properties24. TAX can inhibit tumor cells growth of many types of cancer including nasopharyngeal carcinoma, breast carcinoma, colon carcinoma, cervix carcinoma, ovary carcinoma and so on25–27. TAX significantly suppresses the proliferation and tumor formation of gastric cancer cells by inhibiting EGFR/AKT1 signaling pathway28. TAX also can inhibit RNF31/p53 axis-driven cell proliferation in colorectal cancer by targeting RNF3129. In addition, TAX regulates the expression of Bax, Bcl-2 and cyclin D1 by up-regulating Hint1 transcription, selectively inhibits the proliferation of hepatocellular carcinoma cells, and induces G0/G1 cell cycle arrest and apoptosis30. However, the effect of TAX on the growth of PCa in vitro and in vivo and its mechanism have not yet been revealed.
Our study is aimed at investigating whether TAX can inhibit the proliferation of PCa cells and which signaling pathway and genes closely related to the anti-tumor effect of TAX. Here, we demonstrated that TAX can significantly suppress the proliferation of PCa cells and down-regulate the expression of c-Myc and cyclin D1 in vitro. In addition, we also found that TAX inhibited activation of the PI3K/AKT signaling pathway and reduced the expression of FGFR2 in PCa cells. Finally, we verified TAX evidently inhibited the tumor growth in nude mice and decreased the expression of c-Myc, cyclin D1, p-AKT and FGFR2 in xenograft tumor. These results show that TAX suppresses the proliferation of PCa cells through regulating the PI3K/AKT signaling pathway and FGFR2. Based on this, TAX could be a potential agent for the clinical treatment of PCa.