Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, China.
PLoS One. 2013 Aug 28;8(8):e72478. doi: 10.1371/journal.pone.0072478. eCollection 2013.
Autophagy is a critical mechanism in both cancer therapy resistance and tumor suppression. Monoclonal antibodies have been documented to kill tumor cells via apoptosis, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In this study, we report for the first time that chLym-1, a chimeric anti-human HLA-DR monoclonal antibody, induces autophagy in Raji Non-Hodgkin's Lymphoma (NHL) cells. Interestingly, inhibition of autophagy by pharmacological inhibitors (3-methyladenine and NH4Cl) or genetic approaches (siRNA targeting Atg5) suppresses chLym-1-induced growth inhibition, apoptosis, ADCC and CDC in Raji cells, while induction of autophagy could accelerate cytotoxic effects of chLym-1 on Raji cells. Furthermore, chLym-1-induced autophagy can mediate apoptosis through Caspase 9 activation, demonstrating the tumor-suppressing role of autophagy in antilymphoma effects of chLym-1. Moreover, chLym-1 can activate several upstream signaling pathways of autophagy including Akt/mTOR and extracellular signal-regulated kinase 1/2 (Erk1/2). These results elucidate the critical role of autophagy in cytotoxicity of chLym-1 antibody and suggest a potential therapeutic strategy of NHL therapy by monoclonal antibody chLym-1 in combination with autophagy inducer.
自噬是癌症治疗耐药性和肿瘤抑制的关键机制。已记录单克隆抗体通过细胞凋亡、抗体依赖性细胞毒性 (ADCC) 和补体依赖性细胞毒性 (CDC) 杀死肿瘤细胞。在这项研究中，我们首次报道嵌合抗人 HLA-DR 单克隆抗体 chLym-1 诱导 Raji 非霍奇金淋巴瘤 (NHL) 细胞发生自噬。有趣的是，通过药理学抑制剂（3-甲基腺嘌呤和 NH4Cl）或基因方法（靶向 Atg5 的 siRNA）抑制自噬会抑制 chLym-1 诱导的 Raji 细胞生长抑制、凋亡、ADCC 和 CDC，而诱导自噬可以加速 chLym-1 对 Raji 细胞的细胞毒性作用。此外，chLym-1 诱导的自噬可以通过 Caspase 9 激活介导细胞凋亡，表明自噬在 chLym-1 抗淋巴瘤作用中发挥肿瘤抑制作用。此外，chLym-1 可以激活包括 Akt/mTOR 和细胞外信号调节激酶 1/2 (Erk1/2) 在内的几个自噬上游信号通路。这些结果阐明了自噬在 chLym-1 抗体细胞毒性中的关键作用，并提示通过与自噬诱导剂联合使用单克隆抗体 chLym-1 治疗 NHL 的潜在治疗策略。
