Mechanism of small molecule inhibitors targeting CD147 on abnormal proliferation of triple negative breast cancer by mediating reprogramming of glucose metabolism

FU Zhiguang; LI Hongqi; YAN Maohui; LIU Chen; FAN Chongxi

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Medical Journal of the Chinese People Armed Police Forces ›› 2023, Vol. 34 ›› Issue (4) : 281-286.

Mechanism of small molecule inhibitors targeting CD147 on abnormal proliferation of triple negative breast cancer by mediating reprogramming of glucose metabolism

FU Zhiguang¹, LI Hongqi¹, YAN Maohui¹, LIU Chen¹, FAN Chongxi²

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Abstract

Objective To investigate the effect and mechanism of small molecule inhibitors targeting CD147 on the abnormal proliferation of triple negative breast cancer (TNBC) by mediating reprogramming of glucose metabolism. Methods AC-73,small molecule inhibitor torgeting CD147 was chemically modified to obtain the candidate modification inhibitors HA-08 (a small molecule inhibitor targeting CD147). Biochemical tests related with glucose metabolism were used to evaluate whether HA-08 was involved in the reprogramming process of glucose metabolism in TNBC . The blocking effect of HA-08 on the abnormal proliferation of TNBC cells was verified by WST-1 cell proliferation assay. Bioinformatics analysis combined with molecular biological verification was used to elucidate the molecular mechanism of HA-08 blocking the interaction between CD147 and its ligands. Results Eight candidate compounds were modified preliminarily, and HA-08 was selected as the object of this study through biological verification. Glycolytic experiments showed that HA-08 could up-regulate the extracellular pH level, inhibit the release of TNBC lactic acid and the activity of lactate dehydrogenase (LDH), and reduce the glucose uptake of TNBC cells. Proliferation inhibition assay showed that HA-08 reduced the abnormal proliferation of TNBC cells in a time-concentration dependent manner. Co-ip assay showed that the molecular mechanism of HA-08 was closely related with its blocking of the interaction between CD147 and MCT1. Conclusions HA-08 can inhibit the abnormal proliferation of TNBC cells by blocking the interaction of CD147-MCT1, thereby mediating the reprogramming of TNBC glucose metabolism.

Key words

triple-negative breast cancer / CD147 / small molecule inhibitor / reprogramming of glucose metabolism

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FU Zhiguang, LI Hongqi, YAN Maohui, LIU Chen, FAN Chongxi. Mechanism of small molecule inhibitors targeting CD147 on abnormal proliferation of triple negative breast cancer by mediating reprogramming of glucose metabolism[J]. Medical Journal of the Chinese People Armed Police Forces. 2023, 34(4): 281-286

References

[1] Goldhirsch A, Winer E P, Coates A S,et al. Personalizing the treatment of women with early breast cancer: highlights of the St gallen international expert consensus on the primary therapy of early breast cancer 2013[J]. Ann Oncol, 2013,24(9):2206-2223.
[2] Biswas C, Zhang Y, DeCastro R,et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily[J]. Cancer Res, 1995,55(2):434-439.
[3] 叶辉,徐明,叶曼娜,等. CD147在浸润性乳腺癌分子亚型中的表达与临床意义[J]. 上海交通大学学报(医学版),2016(4): 518-522.
[4] Huang Q, Li J, Xing J,et al. CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway[J]. J Hepatol, 2014,61(4):859-866.
[5] Li J, Huang Q, Long X,et al. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARalpha pathways[J]. J Hepatol, 2015,63(6):1378-1389.
[6] Fu Z G, Wang Y, Wang S,et al. Synthesis and evaluation of a novel small-molecule compound as an Anticancer Inhibitor of CD147[J]. Biomed Environ Sci, 2019,32(9):673-686.
[7] Fu Z G, Wang L, Cui H Y,et al. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells[J]. Oncotarget, 2016,7(8):9429-9447.
[8] Kang M J, Kim H P, Lee K S,et al. Proteomic analysis reveals that CD147/EMMPRIN confers chemoresistance in cancer stem cell-like cells[J]. Proteomics, 2013,13(10-11):1714-1725.
[9] Walters D K, Arendt B K, Jelinek D F. CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells[J]. Cell Cycle, 2013,12(19):3175-3183.
[10] Dent R, Hanna W M, Trudeau M,et al. Pattern of metastatic spread in triple-negative breast cancer[J]. Breast Cancer Res Treat, 2009,115(2):423-428.
[11] Biswas C, Zhang Y, DeCastro R,et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily[J]. Cancer Res, 1995,55(2):434-439.
[12] Cruz C B, Bartolo-Garcia L D, Tizapa-Mendez M D,et al. EMMPRIN is an emerging protein capable of regulating cancer hallmarks[J]. Eur Rev Med Pharmacol Sci, 2022,26(18):6700-6724.[13] Rahat M A. Mini-review: can the metastatic cascade be inhibited by targeting CD147/EMMPRIN to prevent tumor recurrence?[J]. Front Immunol, 2022,13:855978.
[14] Barillari G, Melaiu O, Gargari M,et al. The multiple roles of CD147 in the development and progression of oral squamous cell carcinoma: an overview[J]. Int J Mol Sci, 2022,23(15): 8336.
[15] Kong L M, Liao C G, Zhang Y,et al. A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis[J]. Cancer Res, 2014,74(14):3764-3778.
[16] Li Z, Li D, Li J,et al.Impact of siRNA-mediated down-regulation of CD147 on human breast cancer cells[J]. Chin J Pathol, 2015,44(10):734-738.
[17] Bian H, Zheng J S, Nan G,et al. Randomized trial of ¹³¹I metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation[J]. J Natl Cancer Inst, 2014,106(9): dju239.
[18] Yu X L, Hu T, Du J M, et al. Crystal structure of HAb18G/CD147: implications for immunoglobulin superfamily homophilic adhesion[J]. J Biol Chem, 2008,283(26):18056-18065.
[19] Kalyanaraman B, Cheng G, Hardy M. Therapeutic targeting of tumor cells and tumor immune microenvironment vulnerabilities[J]. Front Oncol, 2022,12:816504.
[20] Wang Y, Qin L, Chen W, et al. Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1[J]. Eur J Med Chem, 2021,226:113806.
[21] Vander H M, Cantley L C, Thompson C B. Understanding the warburg effect: the metabolic requirements of cell proliferation[J]. Science, 2009,324(5930):1029-1033.
[22] Dell’Anno I, Barone E, Mutti L,et al. Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report)[J]. J Transl Med, 2020,18(1):341.
[23] Afonso J, Santos L L, Miranda-Goncalves V,et al. CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance[J]. Mol Carcinog, 2015,54(11):1451-1466.