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

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.

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…Importantly, SL-145 achieves these effects without triggering the HSR. 245 Zhang et al 246 demonstrated that penisuloxazin A reverses the epithelial-mesenchymal transformation of breast cancer cells and enhances the cytotoxicity of natural killer cells against breast cancer cells. Dai et al 247 showed that penicisulfuranol A inhibits multiple HSP90 client proteins, induces apoptosis and inhibits xenograft tumor growth of HCT116 cells both in vitro and in vivo without inducing HSP70.…”

Exploring Mechanism of Actions for Eugenol and Beta- Caryophyllene to Combat Colorectal Cancer Chemotherapy Using Network Pharmacology

“…In addition to their ndings, we found out that eugenol can bind more effectively with the hub proteins such as HSP90AA1, ESR1, CASP3 and IGF-1R than any other selected compounds. HSP90 targets multiple signaling pathways by disrupting metastatic proteins thus, inhibiting epithelial to mesenchymal transition in cancer cells (Anwar et al 2022;Zhang et al 2021). Type-I insulin like growth factor receptor is a tyrosine kinase receptor which is over expressed in many types of cancer processes such as cell growth, cell proliferation, cell differentiation, apoptosis, and angiogenesis.…”

The Chaperone System in Breast Cancer: Roles and Therapeutic Prospects of the Molecular Chaperones Hsp27, Hsp60, Hsp70, and Hsp90

“…High expression levels of Hsp90AA1alpha were associated with the EMT process [ 102 ]. It was observed that, after inhibiting Hsp90 (isoform not specified in the original publication) with penisuloxazin A, the epithelial-cell molecular marker E-cadherin increased, whereas the mesenchymal-cell molecular marker N-cadherin and vimentin and MMP9 proteins decreased significantly [ 103 ]. The examples mentioned in the preceding paragraphs indicate that Hsp90 plays an important role in the stabilization of several proteins that are involved in tumor growth, survival, and progression mechanisms in BC.…”