Department of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.
Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Int J Med Sci. 2021 Apr 26;18(12):2551-2560. doi: 10.7150/ijms.50484. eCollection 2021.
Malignant gliomas are a type of central nervous system cancer with extremely high mortality rates in humans. γ-secretase has been becoming a potential target for cancer therapy, including glioma, because of the involvement of its enzymatic activity in regulating the proliferation and metastasis of cancer cells. In this study, we attempted to determine whether γ-secretase activity regulates E-cadherin to affect glioma cell migration. The human glioma cell lines, including LN18 and LN229, and the γ-secretase inhibitors, including N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and RO4929097, were used in this study. It was shown that γ-secretase activity inhibition by DAPT and RO4929097 could promote LN18 and LN229 glioma cell migration via downregulating E-cadherin mRNA and protein expressions, but not via affecting E-cadherin protein processing. In addition, γ-secretase activity inhibition was regulated by bone morphogenetic proteins-independent Smad5 activation in glioma cells. Moreover, endogenous Smad1 in glioma cells was found to play an important role in regulating E-cadherin expression and subsequent cell migration but did not affect DAPT-stimulated effects. These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.
恶性神经胶质瘤是一种中枢神经系统癌症，其在人类中的死亡率极高。由于其酶活性参与调节癌细胞的增殖和转移，γ-分泌酶已成为癌症治疗（包括神经胶质瘤）的潜在靶点。在这项研究中，我们试图确定 γ-分泌酶活性是否通过调节 E-钙黏蛋白来影响神经胶质瘤细胞的迁移。本研究使用了人神经胶质瘤细胞系，包括 LN18 和 LN229，以及 γ-分泌酶抑制剂，包括 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-S-苯甘氨酸叔丁酯（DAPT）和 RO4929097。结果表明，DAPT 和 RO4929097 通过抑制 γ-分泌酶活性，可下调 E-钙黏蛋白 mRNA 和蛋白表达，从而促进 LN18 和 LN229 神经胶质瘤细胞的迁移，但不影响 E-钙黏蛋白蛋白加工。此外，γ-分泌酶活性受骨形态发生蛋白非依赖性 Smad5 激活的调节。此外，还发现内源性 Smad1 在神经胶质瘤细胞中在调节 E-钙黏蛋白表达和随后的细胞迁移中发挥重要作用，但不影响 DAPT 刺激的作用。这些结果有助于进一步阐明控制神经胶质瘤细胞恶性的 γ-分泌酶活性调节的分子机制。因此，关于在抑制 γ-分泌酶活性过程中 Smad1/5 活性上调及其随后的 E-钙黏蛋白下调在神经胶质瘤发生中的潜在作用的信息，对于未来的研究具有重要意义。
