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

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.

• Authors: Shan Zhu, Lizhi Cao, Yan Yu, Liangchun Yang, Minghua Yang, Ke Liu, Jun Huang, Rui Kang, Kristen M Livesey, Daolin Tang
• Journal: Autophagy (Autophagy) Vol. 9 Issue 3 Pg. 317-27 (Mar 2013) ISSN: 1554-8635 [Electronic] United States
• PMID: 23242206 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, therapy)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction
• Transcription Factor RelA (metabolism)