PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial-Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro.

Aotong Zhang,Dehai Li,Jing Li,Guojian Zhang,Xin Qi,Fu Du

doi:10.3390/md19020117

Abstract

Metastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In the present study, we investigated the inhibitory effect of penisuloxazin A (PNSA), a novel C- terminal inhibitor of HSP90, on metastasis of breast cancer cells and related mechanism in vitro. We found that PNSA obviously affected adhesion, migration, and invasion of triple-negative breast cancer (TNBC) MDA-MB-231 cells and Trastuzumab-resistant JIMT-1 cells. Furthermore, PNSA was capable of reversing epithelial–mesenchymal transformation (EMT) of MDA-MB-231 cells with change of cell morphology. PNSA increases E-cadherin expression followed by decreasing amounts of N-cadherin, vimentin, and matrix metalloproteinases9 (MMP9) and proteolytic activity of matrix metalloproteinases2 (MMP2) and MMP9. Comparatively, the N-terminal inhibitor of HSP90 17-allyl-17-demethoxygeldanamycin (17-AAG) had no effect on EMT of MDA-MB-231 cells. PNSA was uncovered to reduce the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) proteins and thereby inhibiting their downstream signaling transductions by inhibition of HSP90. In addition, PNSA reduced the expression of programmed cell death-ligand 1 (PD-L1) to promote natural killer (NK) cells to kill breast cancer cells with a dose far less than that of cytotoxicity to NK cell itself, implying the potential of PNSA to enhance immune surveillance against metastasis in vivo. All these results indicate that PNSA is a promising anti-metastasis agent worthy of being studied in the future.

Highlights

Introduction published maps and institutional affilBreast cancer is the most malignant and major cause of cancer-related deaths among women worldwide [1], which is classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features
To evaluate the antimetastatic activity of penisuloxazin A (PNSA), we first assessed the inhibitory effects of PNSA on the migration and invasion of MDA-MB-231 cells, triple-negative breast cancer cells, by the wound healing and the transwell
PNSA meaningfully inhibited inhibited invasive capabilities of MDA-MB-231 cells withcells inhibitory rates of 50.62% and 24.88% at indicated concentrations of PNSA (Figure 2C). 17-allyl-17rates of 50.62% and 24.88% at indicated concentrations of PNSA (Figure 2C). 17-allyl-17demethoxygeldanamycin (17-AAG) is a well-known N-terminal inhibitor of heat shock protein 90 (HSP90), we demethoxygeldanamycin (17-AAG) is a well-known N-terminal inhibitor of HSP90, we found that 17-AAG suppressed the migration and invasion of MDA-MB-231 cells dosefound that 17-AAG suppressed the migration and invasion of MDA-MB-231 cells dosedependently

Summary

Introduction

Breast cancer is the most malignant and major cause of cancer-related deaths among women worldwide [1], which is classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features. Therapy strategies vary according to the classification, including endocrine modulators, agents that target estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) such as tamoxifen and trastuzumab. Much progress has been made in early detection and better treatment of breast cancer, leading to improved survival. It is reported that 20–30% of breast cancer patients may develop metastases after diagnosis and primary tumor treatment, and approximately 90% of cancer-related deaths are attributed to metastasis [3,4]. TNBC accounts for about 16% of all breast cancers, and is more aggressive than iations

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