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

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Oct 28

PMID 37893115

Authors

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

Affiliations

Soon will be listed here.

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 . 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.

References

Huynh J, Chand A, Gough D, Ernst M . Therapeutically exploiting STAT3 activity in cancer - using tissue repair as a road map. Nat Rev Cancer. 2018; 19(2):82-96. DOI: 10.1038/s41568-018-0090-8. View

Bhattacharya S, Ray R, Johnson L . STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J. 2005; 392(Pt 2):335-44. PMC: 1316269. DOI: 10.1042/BJ20050465. View

Sarfraz A, Rasul A, Sarfraz I, Shah M, Hussain G, Shafiq N . Hispolon: A natural polyphenol and emerging cancer killer by multiple cellular signaling pathways. Environ Res. 2020; 190:110017. PMC: 7406431. DOI: 10.1016/j.envres.2020.110017. View

Merikhian P, Eisavand M, Farahmand L . Triple-negative breast cancer: understanding Wnt signaling in drug resistance. Cancer Cell Int. 2021; 21(1):419. PMC: 8353874. DOI: 10.1186/s12935-021-02107-3. View

Almansour N . Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022; 9:836417. PMC: 8824427. DOI: 10.3389/fmolb.2022.836417. View

Hsin M, Hsieh Y, Wang P, Ko J, Hsin I, Yang S . Hispolon suppresses metastasis via autophagic degradation of cathepsin S in cervical cancer cells. Cell Death Dis. 2017; 8(10):e3089. PMC: 5680581. DOI: 10.1038/cddis.2017.459. View

Balaji N, Ramani M, Viana A, Sanglard L, White J, Mulabagal V . Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs. Bioorg Med Chem. 2015; 23(9):2148-2158. PMC: 4398655. DOI: 10.1016/j.bmc.2015.03.002. View

Chang W, Liu L, Hsiao C, Su C, Wang H, Ji H . The contributions of the tissue inhibitor of metalloproteinase-1 genotypes to triple negative breast cancer risk. Biomedicine (Taipei). 2016; 6(1):4. PMC: 4752549. DOI: 10.7603/s40681-016-0004-6. View

Robson M, Tung N, Conte P, Im S, Senkus E, Xu B . OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019; 30(4):558-566. PMC: 6503629. DOI: 10.1093/annonc/mdz012. View

10.

Hsieh Y, Dai Y, Cheng K, Yang W, Ramani M, Subbaraju G . Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether. Biomedicines. 2023; 11(9). PMC: 10526010. DOI: 10.3390/biomedicines11092530. View

11.

Ravindran J, Subbaraju G, Ramani M, Sung B, Aggarwal B . Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro. Biochem Pharmacol. 2010; 79(11):1658-66. PMC: 2846970. DOI: 10.1016/j.bcp.2010.01.033. View

12.

Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014; 14(11):736-46. DOI: 10.1038/nrc3818. View

13.

Cheng Y, Li S, Chuang W, Li C, Chen G, Chang C . Blockade of STAT3 Signaling Contributes to Anticancer Effect of 5-Acetyloxy-6,7,8,4'-Tetra-Methoxyflavone, a Tangeretin Derivative, on Human Glioblastoma Multiforme Cells. Int J Mol Sci. 2019; 20(13). PMC: 6651290. DOI: 10.3390/ijms20133366. View

14.

Ullah M . Breast Cancer: Current Perspectives on the Disease Status. Adv Exp Med Biol. 2019; 1152:51-64. DOI: 10.1007/978-3-030-20301-6_4. View

15.

Fincham V, Frame M, Haefner B, Unlu M, Wyke A, Wyke J . Functions of the v-Src protein tyrosine kinase. Cell Biol Int. 1994; 18(5):337-44. DOI: 10.1006/cbir.1994.1083. View

16.

Bromberg J, Wrzeszczynska M, Devgan G, Zhao Y, Pestell R, Albanese C . Stat3 as an oncogene. Cell. 1999; 98(3):295-303. DOI: 10.1016/s0092-8674(00)81959-5. View

17.

Paul M, Kumar Panda M, Thatoi H . Developing Hispolon-based novel anticancer therapeutics against human (NF-κβ) using approach of modelling, docking and protein dynamics. J Biomol Struct Dyn. 2018; 37(15):3947-3967. DOI: 10.1080/07391102.2018.1532321. View

18.

Islam M, Ali E, Khan I, Shaw S, Uddin S, Rouf R . Anticancer Perspectives on the Fungal-Derived Polyphenolic Hispolon. Anticancer Agents Med Chem. 2020; 20(14):1636-1647. DOI: 10.2174/1871520620666200619164947. View

19.

Chen L, Kuo W, Tsai M, Chen P, Hsiao C, Chuang E . Identification of prognostic genes for recurrent risk prediction in triple negative breast cancer patients in Taiwan. PLoS One. 2011; 6(11):e28222. PMC: 3226667. DOI: 10.1371/journal.pone.0028222. View

20.

Kohale I, Yu J, Zhuang Y, Fan X, Reddy R, Sinnwell J . Identification of Src Family Kinases as Potential Therapeutic Targets for Chemotherapy-Resistant Triple Negative Breast Cancer. Cancers (Basel). 2022; 14(17). PMC: 9454481. DOI: 10.3390/cancers14174220. View