Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics.

Abstract

Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.

• Authors: Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka, Toyomasa Katagiri
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 1821 (05 12 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28500289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARFGEF3 protein, human
• Antineoplastic Agents
• Cell-Penetrating Peptides
• ERAP peptide
• ESR1 protein, human
• Estrogen Receptor alpha
• Guanine Nucleotide Exchange Factors
• PHB2 protein, human
• Phb2 protein, mouse
• Prohibitins
• Repressor Proteins
• Estradiol

Topics

• Amino Acid Sequence
• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell-Penetrating Peptides (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Estradiol (metabolism)
• Estrogen Receptor alpha (metabolism)
• Female
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Molecular Structure
• Prohibitins
• Protein Binding
• Repressor Proteins (metabolism)
• Signal Transduction (drug effects)