Autophagy plays a critical role in ChLym-1-induced cytotoxicity of non-hodgkin's lymphoma cells

PLoS One. 2013 Aug 28;8(8):e72478. doi: 10.1371/journal.pone.0072478. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonium Chloride / pharmacology
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Lymphoma, Non-Hodgkin
  • MAP Kinase Signaling System
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Sirolimus / pharmacology

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Ammonium Chloride
  • Sirolimus

Grants and funding

This work was supported by Shanghai Science and Technology Funds (11431920104)[http://www.stcsm.gov.cn/] and National Science and Technology Major Project for Drug Discovery of Ministry of Science and Technology of China (2011ZX09102-001-27) [http://www.most.gov.cn/tztg/index.htm]. The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of manuscript.