PUMA and BIM Are Required for Oncogene Inactivation–Induced Apoptosis

Sci. Signal., 26 March 2013
Vol. 6, Issue 268, p. ra20
DOI: 10.1126/scisignal.2003483

PUMA and BIM Are Required for Oncogene Inactivation–Induced Apoptosis

  1. Gregory R. Bean1,2,
  2. Yogesh Tengarai Ganesan1,
  3. Yiyu Dong1,
  4. Shugaku Takeda1,
  5. Han Liu1,
  6. Po M. Chan1,
  7. Yafen Huang1,
  8. Lewis A. Chodosh3,
  9. Gerard P. Zambetti4,
  10. James J.-D. Hsieh1,5, and
  11. Emily H.-Y. Cheng1,6,7,*
  1. 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  2. 2Division of Biology & Biomedical Sciences, Washington University, St. Louis, MO 63110, USA.
  3. 3Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  4. 4St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
  5. 5Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  6. 6Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  7. 7Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
  1. *Corresponding author. E-mail: chenge1{at}mskcc.org

Abstract

The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called “oncogene addiction.” We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal–regulated protein kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)–AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFRL858R-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism–based anticancer strategies.

Citation:

G. R. Bean, Y. T. Ganesan, Y. Dong, S. Takeda, H. Liu, P. M. Chan, Y. Huang, L. A. Chodosh, G. P. Zambetti, J. J. Hsieh, and E. H. Cheng, PUMA and BIM Are Required for Oncogene Inactivation–Induced Apoptosis. Sci. Signal. 6, ra20 (2013).

The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics
A. N. Hata, J. A. Engelman, and A. C. Faber
Cancer Discovery 5, 475-487 (1 May 2015)

Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways
J. A. Engelman, and A. C. Faber
elife 4, e06132-e06132 (1 January 2015)

Expression of PUMA in Follicular Granulosa Cells Regulated by FoxO1 Activation During Oxidative Stress
Z.-Q. Liu, M. Shen, W.-J. Wu, B.-J. Li, Q.-N. Weng, M. Li, and H.-L. Liu
Reproductive Sciences 0, 1933719114556483v1-1933719114556483 (25 November 2014)

The Essential Role of p53-up-regulated Modulator of Apoptosis (Puma) and Its Regulation by FoxO3a Transcription Factor in {beta}-Amyloid-induced Neuron Death
R. Akhter, P. Sanphui, and S. C. Biswas
J Biol Chem 289, 10812-10822 (11 April 2014)

Evaluation of the BH3-only Protein Puma as a Direct Bak Activator
H. Dai, Y.-P. Pang, M. Ramirez-Alvarado, and S. H. Kaufmann
J Biol Chem 289, 89-99 (3 January 2014)

BIM, PUMA, and the Achilles' Heel of Oncogene Addiction
A. Roulston, W. J. Muller, and G. C. Shore
Sci Signal 6, pe12-pe12 (26 March 2013)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882