Inactive ERBB receptors cooperate with reactive oxygen species to suppress cancer progression

Matthew R. Hart, Hsin Yuan Su, Derrick Broka, Aarthi Goverdhan, Joyce Schroeder

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The ERBB receptors are a family of heterodimerization partners capable of driving transformation and metastasis. While the therapeutic targeting of single receptors has proven efficacious, optimal targeting of this receptor family should target all oncogenic members simultaneously. The juxtamembrane domains of ERBB1, ERBB2, and ERBB3 are highly conserved and control various aspects of ERBB-dependent biology. In an effort to block those functions, we have targeted this domain with decoy peptides synthesized in tandem with a cell-penetrating peptide, termed EJ1. Treatment with EJ1 induces cell death, promotes the formation of inactive ERBB multimers, and results in simultaneous reduction of ERBB1, ERBB2, and ERBB3 activation. Treatment also results in the activation of myosin light chain-dependent cell blebbing while inactivating CaMKII signaling, coincident with the induction of cell death. EJ1 also directly translocates to mitochondria, correlating with a loss of mitochondrial membrane potential and production of reactive oxygen species. Finally, treatment of a mouse model of breast cancer with EJ1 results in the inhibition of tumor growth and metastasis without associated toxicities in normal cells. Overall, these data demonstrate that a portion of the ERBB jxm domain, when used as an intracellular decoy, can inhibit tumor growth and metastasis, representing a novel anticancer therapeutic.

Original languageEnglish (US)
Pages (from-to)1996-2007
Number of pages12
JournalMolecular Therapy
Volume21
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Reactive Oxygen Species
Neoplasm Metastasis
Cell Death
Cell-Penetrating Peptides
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Neoplasms
Myosin Light Chains
Mitochondrial Membrane Potential
Blister
Growth
Mitochondria
Breast Neoplasms
Peptides
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Inactive ERBB receptors cooperate with reactive oxygen species to suppress cancer progression. / Hart, Matthew R.; Su, Hsin Yuan; Broka, Derrick; Goverdhan, Aarthi; Schroeder, Joyce.

In: Molecular Therapy, Vol. 21, No. 11, 11.2013, p. 1996-2007.

Research output: Contribution to journalArticle

Hart, Matthew R. ; Su, Hsin Yuan ; Broka, Derrick ; Goverdhan, Aarthi ; Schroeder, Joyce. / Inactive ERBB receptors cooperate with reactive oxygen species to suppress cancer progression. In: Molecular Therapy. 2013 ; Vol. 21, No. 11. pp. 1996-2007.
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