Zhang Aotong, Qi Xin, Du Fu, Zhang Guojian, Li Dehai, Li Jing
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Open Studio for Druggability Research of Marine Natural Products, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
Mar Drugs. 2021 Feb 20;19(2):117. doi: 10.3390/md19020117.
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.
转移是乳腺癌患者死亡的主要原因，因此迫切需要开发新的有效治疗方法来抑制癌症转移。侵袭性乳腺癌组织中热休克蛋白90（HSP90）的表达水平高于相邻的非癌组织。在本研究中，我们研究了新型HSP90 C端抑制剂阴茎草素A（PNSA）对乳腺癌细胞转移的抑制作用及其体外相关机制。我们发现PNSA明显影响三阴性乳腺癌（TNBC）MDA-MB-231细胞和曲妥珠单抗耐药JIMT-1细胞的黏附、迁移和侵袭。此外，PNSA能够通过改变细胞形态逆转MDA-MB-231细胞的上皮-间质转化（EMT）。PNSA增加E-钙黏蛋白的表达，随后降低N-钙黏蛋白、波形蛋白和基质金属蛋白酶9（MMP9）的含量以及基质金属蛋白酶2（MMP2）和MMP9的蛋白水解活性。相比之下，HSP90的N端抑制剂17-烯丙基-17-去甲氧基格尔德霉素（17-AAG）对MDA-MB-231细胞的EMT没有影响。研究发现，PNSA可降低表皮生长因子受体（EGFR）和成纤维细胞生长因子受体（FGFR）蛋白的稳定性，从而通过抑制HSP90抑制其下游信号转导。此外，PNSA降低程序性细胞死亡配体1（PD-L1）的表达，以促进自然杀伤（NK）细胞以远低于对NK细胞自身细胞毒性的剂量杀死乳腺癌细胞，这意味着PNSA在体内增强对转移的免疫监视的潜力。所有这些结果表明，PNSA是一种有前景的抗转移药物，值得未来进一步研究。
