Inhibiting autophagy potentiates the anticancer activity of IFN1@/IFNα in chronic myeloid leukemia cells

Autophagy. 2013 Mar;9(3):317-27. doi: 10.4161/auto.22923. Epub 2012 Dec 14.

Abstract

IFN1@ (interferon, type 1, cluster, also called IFNα) has been extensively studied as a treatment for patients with chronic myeloid leukemia (CML). The mechanism of anticancer activity of IFN1@ is complex and not well understood. Here, we demonstrate that autophagy, a mechanism of cellular homeostasis for the removal of dysfunctional organelles and proteins, regulates IFN1@-mediated cell death. IFN1@ activated the cellular autophagic machinery in immortalized or primary CML cells. Activation of JAK1-STAT1 and RELA signaling were required for IFN1@-induced expression of BECN1, a key regulator of autophagy. Moreover, pharmacological and genetic inhibition of autophagy enhanced IFN1@-induced apoptosis by activation of the CASP8-BID pathway. Taken together, these findings provide evidence for an important mechanism that links autophagy to immunotherapy in leukemia.

Keywords: IFN1@; apoptosis; autophagy; chronic myeloid leukemia; immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Autophagy*
  • Cell Death
  • HL-60 Cells
  • Homeostasis
  • Humans
  • Immunotherapy / methods
  • Interferon-alpha / pharmacology*
  • Janus Kinase 1 / metabolism
  • Jurkat Cells
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factor RelA / metabolism

Substances

  • Antineoplastic Agents
  • Interferon-alpha
  • RELA protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Transcription Factor RelA
  • JAK1 protein, human
  • Janus Kinase 1