Abstract
The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical “osmotic engine model”. In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1D324K overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.
Highlights
The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer, which is characterized by lack expression of estrogen receptor (ER) and progesterone receptor (PR), and nonamplification of human epidermal growth factor receptor 2 (HER2)[1,2]
Systemic treatment against TNBC remains limited with the conventional chemotherapy as the mainstay, because patients with triple-negative disease do not benefit from endocrine therapy or anti-HER2-targeted therapy, which have been widely applied in the setting of ER/PR-positive or HER2-positive breast cancers with improved prognosis[1,2,3]
Aquaporin 1 (AQP1) is upregulated in triple-negative breast carcinoma and associated with poor survival To determine the expression profile of AQP1 in invasive ductal breast carcinoma (IDC), the Finak’s cohort[28] was analyzed using
Summary
The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer, which is characterized by lack expression of estrogen receptor (ER) and progesterone receptor (PR), and nonamplification of human epidermal growth factor receptor 2 (HER2)[1,2]. The triple-negative phenotype is universally acknowledged to be responsible for the higher rates of relapse, metastasis, and mortality compared to other breast cancer subtypes. Even worse is that some TNBC subsets fail to respond to chemotherapy[4], necessitating an in-depth understanding of TNBC-specific signaling pathways and a de novo exploration of biomarker-sensitive therapeutic strategies. AQP1 may behave as an oncogenic biomarker for numerous types of cancer that is able to sustain tumor pathogenesis through facilitating cell proliferation, migration, and angiogenesis[8,9,10,11]. The exact effect of AQP1 on TNBC cell death evasion and the specific signaling pathway are still far from understood
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