Scoparone attenuates PD-L1 expression in human breast cancer cells by MKP-3 upregulation

Abstract

Breast cancer is a frequently occurring malignant tumor that is one of the leading causes of cancer-related deaths in women worldwide. Monoclonal antibodies that block programed cell death 1 (PD-1)/programed cell death ligand 1 (PD-L1) – a typical immune checkpoint – are currently the recommended standard therapies for many advanced and metastatic tumors such as triple-negative breast cancer. However, some patients develop drug resistance, leading to unfavorable treatment outcomes. Therefore, other approaches are required for anticancer treatments, such as downregulation of PD-L1 expression and promotion of degradation of PD-L1. Scoparone (SCO) is a bioactive compound isolated from Artemisia capillaris that exhibits antitumor activity. However, the effect of SCO on PD-L1 expression in cancer has not been confirmed yet. This study aimed to evaluate the role of SCO in PD-L1 expression in breast cancer cells in vitro. Our results show that SCO downregulated PD-L1 expression in a dose-dependent manner, via AKT inhibition. Interestingly, SCO treatment did not alter PTEN expression, but increased the expression of mitogen-activated protein kinase phosphatase-3 (MKP-3). In addition, the SCO-induced decrease in PD-L1 expression was reversed by siRNA-mediated MKP-3 knockdown. Collectively, these findings suggest that SCO inhibited the expression of PD-L1 in breast cancer cells by upregulating MKP-3 expression. Therefore, SCO may serve as an innovative combinatorial agent for cancer immunotherapy.

Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure–Activity Relationships

“…In triple-negative breast cancer cells (MDA-MB-231), osthole induced apoptosis by suppressing STAT3 and arresting the cell cycle at the G2/M phase, significantly decreased the tumour volume in MDA-MB-231 breast cancer cell xenografts in nude mice [ 29 ]. Scoparone, found in the leaves and stem of the Artemisia capillaris , downregulates the PD-L1 expression in dose-dependent manner and upregulates the MKP-3 expression [ 30 ]. Scoparone inhibits breast cancer cell survival by inhibiting the intercellular NF-κB signalling, which is associated with the SNHG12/ miR-140-3p /TRAF2 axis [ 31 ].…”