σ-2受体激动剂抑制肿瘤细胞增殖分子机制的研究进展

Research progress in the mechanisms of σ-2 receptor agonists inducing tumor cell death

关键词:  σ-2受体  肿瘤  凋亡  溶酶体通透化

Key words:  σ-2 receptors  neoplasms  apoptosis  lysosome membrane permeablization

摘要:

σ-2受体作为一种膜受体，广泛分布于细胞及各细胞器膜表面，其在肿瘤生物学中的研究价值正得到进一步证实。其在处于高增殖期肿瘤细胞表达量是正常组织细胞的10倍，因此其特异性受体激动剂在肿瘤中更容易通过凋亡或非凋亡手段诱导细胞死亡。σ-2受体激动剂可以激活半胱天冬酶3(caspase-3)依赖的线粒体凋亡通路，但抑制caspase-3并不能完全逆转激动剂诱导的细胞死亡。其影响肿瘤细胞内质网钙离子释放，激活PKC通路，同时诱导细胞产生过多活性氧自由基（ROS),从而改变溶酶体膜通透性，诱导溶酶体内各种组织蛋白酶泄露和改变溶酶体内部酸性环境，导致保护性自噬泡的形成，而过量的自噬最终导致细胞程序性细胞死亡。不同受体激动剂影响不同细胞周期蛋白的表达，诱导肿瘤细胞凋亡，并把肿瘤阻滞在不同的细胞周期。本文主要对σ-2受体激动剂诱导肿瘤细胞程序性细胞死亡机制进行了综述，加深其在肿瘤中作用的认识。

Abstract:

As an unique class of membrane receptors,σ-2(Sigma-2) receptors are widely expressed in the organelle membranes and have been proven to be an important protein in the field of cancer biology.σ-2 receptors have been observed 10-fold higher density in proliferating tumor cells than normal cells,which indicate thatσ-2 receptor agonists are more capable of killing tumor cells via apoptotic and non-apoptotic mechanisms.σ-2 agonists can active caspase-3,a key proponent of mitochondria apoptosis pathway,while caspase inhibitor can not completely inhibit the cytotoxicity of σ-2 agonists.σ-2 agonists have been shown to stimulate rapid and transient Ca2+ release from endoplasmic reticulum and active the PKC pathway,meanwhile,it can induce tumor cells generate a large amount of reactive oxygen species(ROS) and influence lysosome membrane permeablization,that would lead to a leakage of cathepsins to cytosol and disruption of the lysosomal PH gradient.This disruption is sufficient to active the autophagic signaling,and agonists-induced autophagosome accumulation servers a cytoprotective function at the early time，while excessive accumulation finally lead program cells death.Different agonists may induce cell death by disrupting different cyclins and impairing cell-cycle progression.This article reviews the mechanisms ofσ-2 agonists inducing tumor cells death and helps us further understand the functions ofσ-2 receptor in cancer.