Liao Chih-Pin, Hsieh Ya-Chu, Lu Chien-Hsing, Dai Wen-Chi, Yang Wei-Ting, Cheng Kur-Ta, Ramani Modukuri V, Subbaraju Gottumukkala V, Chang Chia-Che
Division of General Surgery, Department of Surgery, Kuang Tien General Hospital, Taichung 433401, Taiwan.
Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung 402202, Taiwan.
Biomedicines. 2023 Oct 10;11(10):2742. doi: 10.3390/biomedicines11102742.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with few treatment options. A promising TNBC treatment approach is targeting the oncogenic signaling pathways pivotal to TNBC initiation and progression. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving TNBC malignant transformation, highlighting STAT3 as a promising TNBC therapeutic target. Methoxyhispolon Methyl Ether (MHME) is an analog of Hispolon, an anti-cancer polyphenol found in the medicinal mushroom . Still, MHME's anti-cancer effects and mechanisms remain unknown. Herein, we present the first report about MHME's anti-TNBC effect and its action mechanism. We first revealed that MHME is proapoptotic and cytotoxic against human TNBC cell lines HS578T, MDA-MB-231, and MDA-MB-463 and displayed a more potent cytotoxicity than Hispolon's. Mechanistically, MHME suppressed both constitutive and interleukin 6 (IL-6)-induced activation of STAT3 represented by the extent of tyrosine 705-phosphorylated STAT3 (p-STAT3). Notably, MHME-evoked apoptosis and clonogenicity impairment were abrogated in TNBC cells overexpressing a dominant-active mutant of (STAT3-C); supporting the blockade of STAT3 activation is an integral mechanism of MHME's cytotoxic action on TNBC cells. Moreover, MHME downregulated BCL-2 in a STAT3-dependent manner, and TNBC cells overexpressing BCL-2 were refractory to MHME-induced apoptosis, indicating that BCL-2 downregulation is responsible for MHME's proapoptotic effect on TNBC cells. Finally, MHME suppressed SRC activation, while overexpression rescued p-STAT3 levels and downregulated apoptosis in MHME-treated TNBC cells. Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，治疗选择有限。一种有前景的TNBC治疗方法是针对在TNBC起始和进展中起关键作用的致癌信号通路。信号转导和转录激活因子3（STAT3）的失调激活是驱动TNBC恶性转化的基础，这突出了STAT3作为一个有前景的TNBC治疗靶点。甲氧基组蛋白甲基醚（MHME）是组蛋白的类似物，组蛋白是一种在药用蘑菇中发现的抗癌多酚。然而，MHME的抗癌作用及其机制仍不清楚。在此，我们首次报道了MHME的抗TNBC作用及其作用机制。我们首先发现，MHME对人TNBC细胞系HS578T、MDA-MB-231和MDA-MB-463具有促凋亡和细胞毒性作用，并且比组蛋白表现出更强的细胞毒性。从机制上讲，MHME抑制了以酪氨酸705磷酸化的STAT3（p-STAT3）水平为代表的组成型和白细胞介素6（IL-6）诱导的STAT3激活。值得注意的是，在过表达显性活性突变体（STAT3-C）的TNBC细胞中，MHME诱导的凋亡和克隆形成能力受损得到了挽救；这支持了STAT3激活的阻断是MHME对TNBC细胞细胞毒性作用的一个重要机制。此外，MHME以STAT3依赖的方式下调BCL-2，而过表达BCL-2的TNBC细胞对MHME诱导的凋亡具有抗性，这表明BCL-2的下调是MHME对TNBC细胞促凋亡作用的原因。最后，MHME抑制SRC激活，而SRC过表达恢复了p-STAT3水平，并下调了MHME处理的TNBC细胞中的凋亡。总体而言，我们得出结论，MHME通过阻断SRC/STAT3/BCL-2促生存轴引发TNBC细胞凋亡。我们的研究结果表明了将MHME用作TNBC化疗药物的潜力。
