Elucidation of new functions of cancer-specific BIG3 protein for drug discovery

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07643
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: AIBARA Hitoshi 徳島大学, 先端酵素学研究所, 特任助教 (80587717)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ミトコンドリア

Outline of Final Research Achievements

We demonstrate that Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) large complex consists of Prohibitin 2 (PHB2), a pleiotropic　mitochondrial regulator and several mitochondrial factors maintaining mitochondrial structure and function in triple-negative breast cancer (TNBC) cells. Crucially, either BIG3 knockdown or treatment with a competitive inhibitory peptide (stERAP) targeting BIG3-PHB2 interaction caused abnormal elongation of mitochondria substantially dissimilar to mitochondrial fusion, leading to drastic inhibition of TNBC cell growth. Remarkably, stERAP dissociates not only PHB2 but also other BIG3 interactors from BIG3, resulting in the functional deficiencies of mitochondria. Our results strongly suggest that BIG3 integrates the pathophysiological states of mitochondria, implying the BIG3-PHB2 axis as a potential target for TNBC therapy.

Free Research Field

腫瘍生物学・生化学

Academic Significance and Societal Importance of the Research Achievements

エストロゲン受容体、プロゲステロン受容体、HER2いずれも陰性のトリプルネガティブ乳がん（TNBC）は、高再発率かつ予後不良であり、明確な治療法が確立されていないため、新たな治療標的の同定、治療法の革新的アイデアが望まれる。本研究によって、TNBCにおいて、BIG3-PHB2を中心としたミトコンドリア因子巨大ネットワークが、ミトコンドリアの構造・機能維持に必須であり、同時にTNBCの脆弱性であることが示され、新たな治療標的の可能性が期待される。