ATP-binding cassette subfamily A member 5 suppresses pancreatic ductal adenocarcinoma progression and chemoresistance by promoting β-catenin ubiquitin-dependent degradation.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies characterized by poor prognosis and resistance to therapy. Despite the most widely recognized role of ATP binding cassette (ABC) family transporters in multidrug resistance, emerging evidence suggests that ATP-binding cassette transporter A5 (ABCA5) acts as a tumor suppressor. Nevertheless, the role and molecular mechanism of ABCA5 in PDAC have not yet been fully investigated.

METHODS: Using bulk and single-cell transcriptomics data and analysis of 80 clinical PDAC samples, we investigated the expression and clinical significance of ABCA5 in PDAC. In vitro and in vivo functional assays were conducted to explore the influence of ABCA5 on tumor growth, metastasis, and gemcitabine resistance. Immunofluorescence, mass spectrometry, co-immunoprecipitation, and ubiquitination assays were used to identify the direct interactions between factors. Patient-derived organoids (PDOs) were established to investigate the efficacy of ABCA5 overexpression in combination with gemcitabine and PRI-724 (a WNT inhibitor).

RESULTS: Our study for the first time determined ABCA5 as a tumor suppressor in PDAC, and patients with low ABCA5 expression presented a poorer prognosis than those with high ABCA5 expression. Both in vitro and in vivo assays showed that overexpression of ABCA5 suppressed PDAC tumor growth, metastasis to the liver and lungs, as well as resistance to gemcitabine. In contrast, knockdown of ABCA5 had a tumor-promoting effect. Mechanistically, ABCA5 induced β-catenin ubiquitin-dependent degradation by binding to the WD40 repeat domain of BTRC (β-TrCP), a key E3 ubiquitin ligase, thereby inhibiting the WNT pathway. Importantly, PDOs revealed that overexpression of ABCA5 enhanced the treatment efficacy of gemcitabine, notably when combined with PRI-724.

CONCLUSIONS: Collectively, our study demonstrates that ABCA5 is a potential therapeutic target for PDAC and provides a theoretical basis for a new combination therapy of ABCA5 regulation with gemcitabine and WNT inhibitor.