Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China.
Mol Med Rep. 2020 Nov;22(5):3955-3961. doi: 10.3892/mmr.2020.11482. Epub 2020 Sep 2.
Breast cancer is one of the most aggressive malignant tumors in women. According to the expression differences of estrogen receptor, progesterone receptor, human epidermal growth factor receptor‑2 (HER‑2) and cell proliferation antigen Ki‑67, breast cancer can be divided into four molecular subtypes: Luminal A, Luminal B, HER‑2 overexpression and Basal‑like. Yes‑associated protein (YAP), a downstream effector of the Hippo pathway, is overexpressed in human cancers and is associated with proliferation, apoptosis, migration, invasion and resistance to chemotherapy drugs in breast cancer cells. Verteporfin (VP) is used as a photosensitizer in the treatment of neovascular macular degeneration. VP is also identified as an inhibitor of YAP/TEA domain transcription factor (TEAD) interaction in the absence of light activation. However, detailed structural information about VP and YAP interactions is relatively scarce and VP research targeting YAP in different molecular subtypes of breast cancer cells is also rare. The aims of the present study were to structurally describe the VP binding site in the YAP crystal structure and to verify the non‑photoreactive VP effect targeting YAP on the migration of different molecular subtypes of breast cancer cells. The crystal structure of VP and YAP was calculated by AutoDock 4.2 and the result was illustrated using PyMOL. The non‑photoactivated VP effect on the migration of Luminal A MCF‑7, Luminal B BT‑474 and triple‑negative breast cancer BT‑549 breast cancer cells was evaluated by wound healing and Transwell migration experiments. Results from molecular docking experiments demonstrated that VP could interact through hydrogen bonds and hydrophobic interactions with important YAP residues involved in TEADs binding (Gln82, Val84, Met86 and Arg89). Migration experiments revealed that the non‑photoinduced VP could inhibit the migration of different molecular subtypes of breast cancer cells. The results of the present study indicated that VP may be a novel repositioned drug for breast cancer treatment in the future.
乳腺癌是女性最具侵袭性的恶性肿瘤之一。根据雌激素受体、孕激素受体、人表皮生长因子受体-2（HER-2）和细胞增殖抗原 Ki-67 的表达差异，乳腺癌可分为四个分子亚型：Luminal A、Luminal B、HER-2 过表达和基底样。Yes 相关蛋白（YAP）是 Hippo 通路的下游效应物，在人类癌症中过表达，与乳腺癌细胞的增殖、凋亡、迁移、侵袭和化疗药物耐药性有关。维替泊芬（VP）在治疗新生血管性黄斑变性中用作光敏剂。在没有光激活的情况下，VP 也被鉴定为 YAP/TEAD 结构域转录因子（TEAD）相互作用的抑制剂。然而，关于 VP 和 YAP 相互作用的详细结构信息相对较少，针对不同分子亚型乳腺癌细胞中 YAP 的 VP 研究也很少。本研究旨在从结构上描述 YAP 晶体结构中 VP 的结合位点，并验证非光反应性 VP 靶向 YAP 对不同分子亚型乳腺癌细胞迁移的作用。通过 AutoDock 4.2 计算 VP 和 YAP 的晶体结构，并使用 PyMOL 进行说明。通过划痕愈合和 Transwell 迁移实验评估非光激活 VP 对 Luminal A MCF-7、Luminal B BT-474 和三阴性乳腺癌 BT-549 乳腺癌细胞迁移的影响。分子对接实验结果表明，VP 可通过氢键和疏水相互作用与参与 TEAD 结合的 YAP 重要残基（Gln82、Val84、Met86 和 Arg89）相互作用。迁移实验表明，非光诱导的 VP 可抑制不同分子亚型乳腺癌细胞的迁移。本研究结果表明，VP 可能成为未来乳腺癌治疗的一种新型重定位药物。
