Abstract 1753: Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy

Abstract

Abstract The 5-year relative survival rate for triple-negative breast cancer (TNBC) is 77%, which is notably lower than 90%, the overall survival rate for breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. However, patients frequently develop resistance to conventional chemotherapy, greatly compromising the anti-tumor effects of chemodrugs. Therefore, this study is aimed to enhance the effects of chemotherapy. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR post-transcriptionally regulates the stability of the target mRNA by binding to the U- or AU-rich elements (ARE) mainly in the 3’ untranslated region (UTR) of mRNA. In most cases, the binding stabilizes mRNA, thereby enhancing the translation of the encoded protein, many of which are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, and accumulated cytoplasmic expression, are reported to be related to chemoresistance in many types of cancer cells. We hypothesized that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins contributing to chemoresistance.Previously, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. To test our hypothesis, we utilized KH-3 as a tool compound to assess whether HuR inhibition enhances the efficacy of chemotherapy for TNBC cells. We generated a cell sub-line (231-TR) derived from the human TNBC cell line MDA-MB-231 with acquired resistance against docetaxel (TXT). Compared with the parental cell line, 231-TR exhibited similar sensitivity to KH-3 in the MTT-based cytotoxicity assay and the colony formation assay. The in vitro and in vivo combination of KH-3 and TXT synergized in inhibiting cell proliferation and tumor growth of multiple TNBC cell lines. Regarding mechanisms of action, the apoptosis pathway was downregulated and the Wnt signaling pathway was upregulated in 231-TR cells. KH-3 treatment downregulated β-Catenin, involved in promoting cell proliferation, in a time and dose-dependent manner. KH-3 was also identified to induce apoptosis cell death via inhibiting the anti-apoptotic protein BCL2. The cell cycle analysis revealed that KH-3 treatment caused the S phase accumulation. Therefore, the cell proliferation inhibition by KH-3 results from a combination of apoptosis and cell cycle arrest. Furtherly, KH-3 restored the effects of docetaxel in inducing apoptotic cell death in 231-TR cells. Together, this study provides a new strategy to overcome chemotherapy resistance in TNBC cells by functional inhibiting HuR. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny Welch, Xiaoqing Wu, Liang Xu. Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1753.