中药活性成分调节MAPK信号通路抗食管鳞癌的研究进展

Active Ingredients of Chinese Medicine Against Esophageal Squamous Cell Carcinoma by Regulating MAPK Signaling Pathway:A Review

食管鳞癌(ESCC)是中国最主要的食管癌组织学分型,其发病机制复杂,可能与多个基因发生突变及丝裂原活化蛋白激酶(MAPK)通路、磷脂酰肌醇3-激酶(PI3K)通路等失调有关。MAPK信号通路可以被生长因子、原癌基因、氧化应激等激活,从而参与细胞的增殖、分化、迁移、凋亡等生物学功能。越来越多的证据表明MAPK信号通路在ESCC的发生发展中起到重要的作用,有望成为ESCC治疗的有效靶点。经典的MAPK家族包括细胞外信号调节激酶1/2(ERK1/2)、c-Jun氨基末端激酶1/2/3(JNK1/2/3)、p38激酶α/β/γ/δ(p38α/β/γ/δ)和细胞外信号调节激酶5(ERK5),每条通路由3种级联顺序磷酸化激活的蛋白激酶体系构成。其中ERK1/2通路的激活与ESCC的增殖、迁移、耐药及凋亡抑制有关,JNK、p38、ERK5通路似乎表现出双向调节作用,并且存在MAPK内部通路之间的信号整合。食管癌化疗药物往往不良反应较大且易产生耐药性,寻找高效、低毒的药物替代治疗成为一种新的思路。研究发现黄酮类、萜类、生物碱类、皂苷类、酚类等中药活性成分能够通过靶向MAPK通路发挥抗ESCC作用,主要体现在抑制增殖、迁移、侵袭,诱导周期阻滞,促凋亡,逆转耐药等方面。因此该文就MAPK信号通路在ESCC中的调节作用及中药活性成分调节MAPK通路抗ESCC的研究进展进行总结,以期为中药防治食管癌的机制研究和新药开发提供参考。

Esophageal squamous cell carcinoma(ESCC),the predominant histological strain of esophageal cancer in China,is complex in pathogenesis and may be associated with mutations in several genes and dysregulation of the mitogen-activated protein kinase(MAPK)pathway,the phosphatidylinositol 3-kinase(PI3K)pathway,etc.MAPK signaling pathway can be activated by growth factors,proto-oncogenes,and oxidative stress,thus participating in biological functions such as cell proliferation,differentiation,migration,and apoptosis.More evidence shows that the MAPK signaling pathway plays an important role in the occurrence and development of ESCC and is expected to become an effective target for the treatment of ESCC.The classical MAPK family consists of extracellular signal-regulated kinases 1/2(ERK1/2),c-Jun N-terminal kinases 1/2/3(JNK1/2/3),p38α/β/γ/δ,and extracellular signal-regulated kinase 5(ERK5).Each pathway consists of three cascade sequentially phosphorylated and activated protein kinase systems.The activation of the ERK1/2 pathway is related to the proliferation,migration,drug resistance,and apoptosis inhibition of ESCC.JNK,p38,and ERK5 pathways seem to show bidirectional regulation,and there is signal integration between MAPK internal pathways.Chemotherapeutic drugs for esophageal cancer often have side effects and are prone to drug resistance,so it has become a new idea to find effective and low-toxic drug alternatives.Studies have found that flavonoids,terpenoids,alkaloids,saponins,phenols,and other active ingredients in Chinese medicine can play an anti-ESCC effect by targeting the MAPK pathway,which is mainly reflected in inhibiting proliferation,migration,and invasion,inducing cycle arrest,promoting apoptosis,reversing drug resistance,etc.Therefore,this paper reviewed the regulatory role of the MAPK signaling pathway in ESCC and the research progress in active ingredients of Chinese medicine in regulating MAPK pathway against ESCC to provide references for the mechanism research and new drug development of Chinese medicine in the prevention and treatment of esophageal cancer.