Inactive ERBB Receptors Cooperate With Reactive Oxygen Species To Suppress Cancer Progression

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.

Design, Synthesis, and Phenotypic Profiling of Pyrano‐Furo‐Pyridone Pseudo Natural Products

“…However,w en oted that these developmental and metabolism networks are involved in the regulation of reactive oxygen species (ROS) formation. [32] In addition, the fingerprint determined for PFP 14 dk at 30 mm showed 88 %s imilarity to the fingerprint determined for aumitin (19,F igure 3a), ak nown inhibitor of mitochondrial respiration by targeting mitochondrial complex I. [31d] Since these results suggested that pseudo NP 14 dk may modulate mitochondrial function as well, aM ito Stress Test assay was carried out employing the Seahorse XF analyzer as previously reported.…”

The emerging role of CaMKII in cancer

“…Overexpression of CaMKII resulted in inhibition of procaspase-7 and procaspase-8 expression. And the activation of caspase-2, -7, and -8 could be prevented or diminished by overexpression of CaMKII [ 40 ]. Cohen et al[ 41 ] reported that downregulation of ErbB could suppress the CaMKII signaling, which is coincident with the induction of apoptosis in breast and prostate cancer cells.…”

Bifunctional fused polypeptide inhibits the growth and metastasis of breast cancer

“…Targeted fused polypeptides are an emerging hotspot in targeted therapy for breast cancer. 23 , 24 There are a number of studies on the anticancer effect of targeted fused polypeptides in the treatment of breast cancer, including targeting the con-served transmembrane domain of human epidermal growth factor receptors, 25 – 29 glucose-regulated protein 78, 30 transferrin receptor, 31 and p53. 32 These targeted fused polypeptides exhibited a potent cell death inducing effect on tumor cells and a considerable suppressing effect on tumor growth and metastasis, indicating that the targeted fused polypeptide represents a promising targeted therapy strategy.…”