Autophagy inhibition cooperates with erlotinib to induce glioblastoma cell death
Autophagy inhibition cooperates with erlotinib to induce glioblastoma cell death
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DOI：
10.4161/cbt.11.12.15693
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发表时间：
2011-06-15
影响因子：
3.6
通讯作者：
Belloc, Francis
中科院分区：
文献类型：
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作者：
Eimer, Sandrine;Belaud-Rotureau, Marc-Antoine;Belloc, Francis
神经胶质瘤是成人最常见的恶性原发性脑肿瘤。由于对放疗和化疗的固有抵抗力，中位生存期从未超过 12 个月。表皮生长因子受体 (EGFR) 在胶质母细胞瘤 (GBM) 中扩增、过度表达和/或突变，使其成为治疗的合理选择。厄洛替尼是一种 EGFR 激酶抑制剂，与多种癌症的临床反应密切相关。在 U87-MG 和 DBTRG-05MG（两种人胶质母细胞瘤细胞系）中研究了厄洛替尼对细胞增殖的抑制作用和诱导细胞凋亡的作用。在这些细胞系和胶质母细胞瘤的肿瘤组织中研究了几种凋亡相关蛋白的表达。两种细胞系均表达野生型 EGFR，但缺乏 PTEN。厄洛替尼诱导 BIM 蛋白显着积累，但无论 XIAP 减少多少，caspase-3 机制的激活都缺失。此外，在U87-MG中，厄洛替尼促进αB-晶状体蛋白的积累，这是一种能够损害半胱天冬酶激活的小型热休克蛋白。 DBTRG-05MG 被发现缺乏 procaspase-3 且组成型过度表达 α B-晶状体蛋白。同样，在胶质母细胞瘤样本中不断发现 PTEN 和 procaspase-3 缺陷，而 α B-晶状体蛋白表达不一致。在细胞系中，高浓度的厄洛替尼通过不依赖半胱天冬酶的过程诱导细胞死亡，并且在 U87-MG 中证实了自噬过程。自噬的抑制导致厄洛替尼的死亡诱导活性显着增加。这些结果证实胶质母细胞瘤细胞系表现出多种抗凋亡机制，并强调 EGFR 靶向治疗必须与其他抑制剂联合才能实现抗肿瘤作用。
Gliomas are the most common malignant primary brain tumors in adults. The median survival never exceeds 12 months, owing to inherent resistance to both radio and chemotherapies. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in glioblastomas (GBM), making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. Inhibition of cell proliferation and induction of apoptosis by erlotinib were investigated in U87-MG and DBTRG-05MG, two human glioblastoma cell lines. The expression of several apoptosis-related proteins was investigated in these cell lines and in tumoral tissue from glioblastomas. Both cell lines expressed wild-type EGFR but were deficient for PTEN. Erlotinib induced a marked accumulation of the BIM protein, but the activation of caspase-3 machinery was missing, regardless of the decrease in XIAP. Moreover, in U87-MG, erlotinib promoted accumulation of alpha B-crystallin a small heat shock protein capable to impair caspase activation. DBTRG-05MG was found deficient for procaspase-3 and constitutively overexpressed alpha B-crystallin. Similarly, deficiencies in PTEN and procaspase-3 were constantly found in samples from glioblastoma samples, while alpha B-crystallin expression was inconsistent. In cell lines, high concentrations of erlotinib induced cell death through a caspase-independent process and an autophagic process was evidenced in U87-MG. Inhibition of autophagy induced a marked increase in the death-inducing activity of erlotinib. These results confirm that glioblastoma cell lines exhibit several anti-apoptotic mechanisms, and underline that EGFR targeted therapy must be associated to other inhibitors to achieve an antitumoral effect.