Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro

Chih-Pin Liao; Ya-Chu Hsieh; Chien-Hsing Lu; Wen-Chi Dai; Wei-Ting Yang; Kur-Ta Cheng; Modukuri V Ramani; Gottumukkala V Subbaraju; Chia-Che Chang

doi:10.3390/biomedicines11102742

Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro

Biomedicines. 2023 Oct 10;11(10):2742. doi: 10.3390/biomedicines11102742.

Authors

Chih-Pin Liao^{1

2}, Ya-Chu Hsieh³, Chien-Hsing Lu^{2

4}, Wen-Chi Dai⁵, Wei-Ting Yang⁶, Kur-Ta Cheng⁷, Modukuri V Ramani⁸, Gottumukkala V Subbaraju⁸, Chia-Che Chang^{2

3

5

6

9

10

11

12}

Affiliations

¹ Division of General Surgery, Department of Surgery, Kuang Tien General Hospital, Taichung 433401, Taiwan.
² Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung 402202, Taiwan.
³ Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung 402202, Taiwan.
⁴ Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung 407219, Taiwan.
⁵ Doctoral Program in Biotechnology Industrial Innovation and Management, National Chung Hsing University, Taichung 402202, Taiwan.
⁶ Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan.
⁷ Department of Biochemistry and Molecular Cell Biology, Taipei Medical University, Taipei 110301, Taiwan.
⁸ Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India.
⁹ Graduate Institute of Biomedical Sciences, Rong Hsing Translational Medicine Research Center, The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402202, Taiwan.
¹⁰ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413305, Taiwan.
¹¹ Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan.
¹² Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110301, Taiwan.

Abstract

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 Phellinus linteus. 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 (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 v-src 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.

Keywords: BCL-2; SRC; STAT3; apoptosis; hispolon; methoxyhispolon methyl ether; triple-negative breast cancer.

Grants and funding

MOE-112-S-0023-A/The iEGG and Animal Biotechnology Center from the Feature Areas Research Center Program, within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan