| Budget Amount *help |
¥44,460,000 (Direct Cost: ¥34,200,000、Indirect Cost: ¥10,260,000)
Fiscal Year 2024: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2023: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2022: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2021: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2020: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
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| Outline of Final Research Achievements |
We elucidated the functional significance of the BIG3-PHB2 complex in HER2-positive, ER-positive, and TNBC. We found that in HER2-positive cells, the complex localizes to the trans-Golgi network (TGN), where phosphorylation of BIG3 enhances PP1Cα activity via PKA, leading to dephosphorylation and inactivation of PHB2. Treatment with the BIG3-PHB2 interaction inhibitor stERAP releases PHB2, promoting its phosphorylation, nuclear translocation, and transcriptional repression of oncogenic signals. stERAP also disrupts vesicle transport controlled by the TGN-localized complex, suppressing tumor growth. In TNBC, the complex localizes to mitochondria, and stERAP induces mitochondrial elongation defects and apoptosis. Moreover, we developed a long-acting peptide, dstERAP, and revealed its sustained antitumor mechanism. stERAP/dstERAP demonstrated antitumor effects in vitro and in vivo, and may overcome trastuzumab resistance and target difficult cancers like melanoma and pancreatic cancer.
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