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RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis

Zhuming Yin1, Wenlin Chen2, Jian Yin1

  • 1Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin, China.

NPJ Breast Cancer
|May 13, 2021
PubMed

Insights

Receptor-interacting protein kinase 1 (RIPK1) inhibits aggressive triple-negative breast carcinoma (TNBC) progression driven by Aquaporin 1 (AQP1). RIPK1 inactivation by AQP1 promotes TNBC metastasis, highlighting RIPK1 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Signaling

Background:

  • Triple-negative breast carcinoma (TNBC) is an aggressive subtype characterized by poor prognosis.
  • Aberrant cytoplasmic enrichment of Aquaporin 1 (AQP1) in TNBC contributes to tumor cell survival.
  • The non-osmotic roles of cytoplasmic AQP1 in cancer progression are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which cytoplasmic Aquaporin 1 (AQP1) drives triple-negative breast carcinoma (TNBC) progression and metastasis.
  • To investigate the role of receptor-interacting protein kinase 1 (RIPK1) in mediating AQP1-driven TNBC.
  • To identify RIPK1 as a potential therapeutic target for TNBC.

Main Methods:

  • Correlation analysis of AQP1 and RIPK1 expression with TNBC clinical features.
  • Co-immunoprecipitation assays to study AQP1-RIPK1 binding.
  • Genetic manipulation (inhibition and overexpression) of RIPK1 in TNBC cells.
  • Analysis of necroptosis (RIPK1/RIPK3/MLKL) and apoptosis (RIPK1/caspase-8/caspase-3) pathways.
  • Site-directed mutagenesis of RIPK1 (D324 site).

Main Results:

  • AQP1 overabundance and RIPK1 depletion are prevalent in TNBC and associated with aggressive features and poor prognosis.
  • AQP1 binds to RIPK1, inhibiting both necroptosis and apoptosis pathways.
  • Genetic inhibition of RIPK1 enhances AQP1's pro-tumor effects, while RIPK1 overexpression attenuates them.
  • AQP1 facilitates RIPK1 cleavage and inactivation by activating the caspase-8/RIPK1 feedback loop, specifically binding to RIPK1 at the D324 site.
  • Overexpression of a non-cleavable RIPK1 mutant (RIPK1D324K) abrogated RIPK1 inactivation and reduced TNBC cell aggressiveness.

Conclusions:

  • Cytoplasmic AQP1 promotes TNBC progression and metastasis by inactivating RIPK1, thereby inhibiting cell death pathways.
  • RIPK1 acts as a critical negative regulator of AQP1-driven TNBC.
  • Targeting RIPK1 inactivation presents a promising therapeutic strategy for TNBC.

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