고민수 (덕성여자대학교, 연세대학교) | 한빛사논문 > 한빛사

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고민수Minsoo Koh

덕성여자대학교, 연세대학교

Autophagy, Jan 30 2024, | https://doi.org/10.1080/15548627.2024.2305063 ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells

Minsoo Koh ^a,b,†, Hyesol Lim ^a,†, Hao Jin ^a,†, Minjoo Kim ^a, Yeji Hong ^a, Young Keun Hwang ^a, Yunjung Woo ^a, Eun-Sook Kim ^a, Sun Young Kim ^c, Kyung Mee Kim ^a, Hyun Kyung Lim ^a, Joohee Jung ^a, Sujin Kang ^b, Boyoun Park^b, Han-Byoel Lee ^d, Wonshik Han ^d,e, Myung-Shik Lee f, and Aree Moon ^a,*

^aDuksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
^bDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
^cDepartment of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul, Korea
^dDepartment of Surgery, Seoul National University College of Medicine, Seoul, Korea
^eCancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
^fAvison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea

^†These authors contributed equally to this study
^*Corresponding author: correspondence to Aree Moon

Abstract

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A₁ treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-02-01)
연구진국내 연구진
분야 의약학 > 종양의학

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