ONCOLOGY / RESEARCH PAPER
PARP9 knockdown confers protection against chemoresistance and immune escape of breast cancer cells by blocking the PI3K/AKT pathway
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1
The Second Affiliated Hospital of Nanchang University, China
2
The Third Xiangya Hospital, Central South University, China
Submission date: 2022-11-10
Final revision date: 2023-02-07
Acceptance date: 2023-02-18
Online publication date: 2023-03-26
Corresponding author
Lin Wang
The Second Affiliated Hospital of Nanchang University, China
Arch Med Sci 2024;20(4)
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ABSTRACT
Introduction:
This study probes the mechanism of the PARP9/PI3K/AKT/PD-L1 axis in the chemoresistance and immune escape of breast cancer (BRCA) cells.
Material and methods:
The expression of related genes was detected in MCF-7/FUL cells. After MCF-7/FUL cells were treated with sh-PARP9 and/or the PI3K/AKT pathway activator, drug resistance, proliferation, migration, invasion, and apoptosis were measured. Afterward, MCF-7/FUL cells were co-cultured with CD8+ T cells for examining the positive rate and density of MCF-7/FUL cells, the percentage and apoptosis of CD8+ T cells, and the expression of immune-related factors in cell supernatants. Nude mice were subcutaneously injected with sh-PARP9-transfected MCF-7/FUL cells for in vivo validation.
Results:
PARP9 was highly expressed in MCF-7/FUL cells. Sh-PARP9 transfection suppressed cell migration, proliferation, and invasion while accelerating apoptosis in MCF-7/FUL cells, accompanied by downregulated PD-L1, p-PI3K, and p-AKT expression, and reduced IC50 and FUL resistance. After co-culture of MCF-7/FUL cells with CD8+ T cells, the percentage of CD8+ T cells, the expression of immune-related factors in supernatants, and the positive rate of MCF-7/FUL cells increased, while the apoptosis of CD8+ T cells and the density of adherent MCF-7/FUL cells were diminished. These trends were negated by further activating the PI3K/AKT pathway. PARP9 knockdown suppressed xenograft growth, decreased p-PI3K, p-AKT, PD-L1, and Cyclin D1 expression, and augmented p-Cdc2 and cleaved caspase 3 levels in nude mice.
Conclusions:
PARP9 knockdown blocked the PI3K/AKT pathway to downregulate PD-L1, thus depressing chemoresistance and immune escape in BRCA.