Tangeretin inhibits tumor stemness of non-small cell lung cancer by regulating PI3K/AKT/mTOR signaling pathway_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Sai ¹ , WANG Lingjie ¹ , LI Yanli ¹ , LI Peng ¹ , LI Mengjun ¹ , ZHAO Donghua ¹ ,  WANG Yongjie ²

1. Qingdao University, Qingdao, 266071, Shandong, P. R. China;
2. Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266071, Shandong, P. R. China;

Corresponding author：

WANG Yongjie, Email: wstgzy1@163.com

Keywords：

Tangeretin; non-small cell lung cancer; cancer stemness; PI3K/AKT/mTOR signaling pathway

DOI：

10.7507/1007-4848.202203003

Video：

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Objective To study the effect of Tangeretin on non-small cell lung cancer (NSCLC) and the tumor stemness, and to find the molecular mechanism of its effect. Methods We used cell counting and cell cloning experiments to study the effect of Tangeretin on the proliferation of NSCLC cells in vitro. The effect of Tangeretin on the invasion of NSCLC cells was detected by transwell assay. We detected the effect of Tangeretin on the proliferation of NSCLC cells in vivo by nude mouse tumor-bearing experiment. The effect of Tangeretin on tumor stemness of NSCLC cells was detected by self-renew assay, and CD133 and Nanog protein expressions. The expressions of PI3K/AKT/mTOR signaling pathway-related proteins were detected by Western blotting (WB). Results Tangeretin had a good inhibitory effect on the proliferation of NSCLC cells in vivo and in vitro. Cell counting experiment, clonal formation experiment and nude mouse tumor-bearing experiment showed that Tangeretin could inhibit the proliferation activity, clonal formation ability, and tumor size of NSCLC cells in vivo. Self-renew experiments showed that Tangeretin could inhibit the self-renew ability of NSCLC cells. WB experiments showed that Tangeretin inhibited the expressions of tumor stemness markers CD133 and Nanog in NSCLC cells. Tangeretin could inhibit the activation of PI3K/AKT/mTOR signaling pathway-related proteins in NSCLC cells, and the activation of PI3K/AKT/mTOR signaling pathway could partially remit the inhibitory effect of Tangeretin on tumor stemness of NSCLC cells. Conclusion Tangeretin can inhibit the tumor stemness of NSCLC cells, which may be related to the regulation of PI3K/AKT/mTOR signaling pathway.

Citation： WANG Sai, WANG Lingjie, LI Yanli, LI Peng, LI Mengjun, ZHAO Donghua, WANG Yongjie. Tangeretin inhibits tumor stemness of non-small cell lung cancer by regulating PI3K/AKT/mTOR signaling pathway. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(4): 614-621. doi: 10.7507/1007-4848.202203003 Copy

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2.	Jones GS, Baldwin DR. Recent advances in the management of lung cancer. Clin Med (Lond), 2018, 18(Suppl 2): s41-s46.
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10.	Gul HF, Ilhan N, Ilhan N, et al. The combined effect of pomegranate extract and tangeretin on the DMBA-induced breast cancer model. J Nutr Biochem, 2021, 89: 108566.
11.	Bao H, Zheng N, Li Z, et al. Synergistic effect of tangeretin and atorvastatin for colon cancer combination therapy: Targeted delivery of these dual drugs using RGD peptide decorated nanocarriers. Drug Des Devel Ther, 2020, 14: 3057-3068.
12.	Chen KH, Weng MS, Lin JK. Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol, 2007, 73(2): 215-227.
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14.	Li YR, Li S, Ho CT, et al. Tangeretin derivative, 5-acetyloxy-6, 7, 8, 4’-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. Cancer Biol Ther, 2016, 17(1): 48-64.
15.	Roshini A, Jagadeesan S, Arivazhagan L, et al. pH-sensitive tangeretin-ZnO quantum dots exert apoptotic and anti-metastatic effects in metastatic lung cancer cell line. Mater Sci Eng C Mater Biol Appl, 2018, 92: 477-488.
16.	Zhu WB, Xiao N, Liu XJ. Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Oncol Lett, 2018, 15(1): 433-440.
17.	Hermawan A, Putri H, Hanif N, et al. Integrative bioinformatics study of tangeretin potential targets for preventing metastatic breast cancer. Evid Based Complement Alternat Med, 2021, 2021: 2234554.
18.	Mdkhana B, Zaher DM, Abdin SM, et al. Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production. Phytomedicine, 2021, 83: 153470.
19.	Fan S, Xu H, Liu H, et al. Inhibition of cancer cell growth by Tangeretin flavone in drug-resistant MDA-MB-231 human breast carcinoma cells is facilitated via targeting cell apoptosis, cell cycle phase distribution, cell invasion and activation of numerous Caspases. J BUON, 2019, 24(4): 1532-1537.
20.	Pan G, Liu Y, Shang L, et al. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond), 2021, 41(3): 199-217.
21.	Walcher L, Kistenmacher AK, Suo H, et al. Cancer stem cells-origins and biomarkers: Perspectives for targeted personalized therapies. Front Immunol, 2020, 11: 1280.
22.	Heng WS, Gosens R, Kruyt FAE. Lung cancer stem cells: Origin, features, maintenance mechanisms and therapeutic targeting. Biochem Pharmacol, 2019, 160: 121-133.
23.	Pereira CV, Duarte M, Silva P, et al. Polymethoxylated flavones target cancer stemness and improve the antiproliferative effect of 5-fluorouracil in a 3D cell model of colorectal cancer. Nutrients, 2019, 11(2): 326.
24.	Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther, 2020, 5(1): 8.
25.	Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A, 2009, 106(1): 268-273.
26.	Huang EH, Hynes MJ, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res, 2009, 69(8): 3382-3389.

1. Mao Y, Yang D, He J, et al. Epidemiology of lung cancer. Surg Oncol Clin N Am, 2016, 25(3): 439-445.
2. Jones GS, Baldwin DR. Recent advances in the management of lung cancer. Clin Med (Lond), 2018, 18(Suppl 2): s41-s46.
3. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689): 446-454.
4. Patel SA, Weiss J. Advances in the treatment of non-small cell lung cancer: Immunotherapy. Clin Chest Med, 2020, 41(2): 237-247.
5. Eun K, Ham SW, Kim H. Cancer stem cell heterogeneity: Origin and new perspectives on CSC targeting. BMB Rep, 2017, 50(3): 117-125.
6. Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol, 2015, 31: 28-35.
7. Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer, 2013, 13(10): 727-738.
8. Perez-Cornago A, Travis RC, Appleby PN, et al. Fruit and vegetable intake and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer, 2017, 141(2): 287-297.
9. Raza W, Luqman S, Meena A. Prospects of tangeretin as a modulator of cancer targets/pathways. Pharmacol Res, 2020, 161: 105202.
10. Gul HF, Ilhan N, Ilhan N, et al. The combined effect of pomegranate extract and tangeretin on the DMBA-induced breast cancer model. J Nutr Biochem, 2021, 89: 108566.
11. Bao H, Zheng N, Li Z, et al. Synergistic effect of tangeretin and atorvastatin for colon cancer combination therapy: Targeted delivery of these dual drugs using RGD peptide decorated nanocarriers. Drug Des Devel Ther, 2020, 14: 3057-3068.
12. Chen KH, Weng MS, Lin JK. Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol, 2007, 73(2): 215-227.
13. Charoensinphon N, Qiu P, Dong P, et al. 5-demethyltangeretin inhibits human nonsmall cell lung cancer cell growth by inducing G2/M cell cycle arrest and apoptosis. Mol Nutr Food Res, 2013, 57(12): 2103-2111.
14. Li YR, Li S, Ho CT, et al. Tangeretin derivative, 5-acetyloxy-6, 7, 8, 4’-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. Cancer Biol Ther, 2016, 17(1): 48-64.
15. Roshini A, Jagadeesan S, Arivazhagan L, et al. pH-sensitive tangeretin-ZnO quantum dots exert apoptotic and anti-metastatic effects in metastatic lung cancer cell line. Mater Sci Eng C Mater Biol Appl, 2018, 92: 477-488.
16. Zhu WB, Xiao N, Liu XJ. Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Oncol Lett, 2018, 15(1): 433-440.
17. Hermawan A, Putri H, Hanif N, et al. Integrative bioinformatics study of tangeretin potential targets for preventing metastatic breast cancer. Evid Based Complement Alternat Med, 2021, 2021: 2234554.
18. Mdkhana B, Zaher DM, Abdin SM, et al. Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production. Phytomedicine, 2021, 83: 153470.
19. Fan S, Xu H, Liu H, et al. Inhibition of cancer cell growth by Tangeretin flavone in drug-resistant MDA-MB-231 human breast carcinoma cells is facilitated via targeting cell apoptosis, cell cycle phase distribution, cell invasion and activation of numerous Caspases. J BUON, 2019, 24(4): 1532-1537.
20. Pan G, Liu Y, Shang L, et al. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond), 2021, 41(3): 199-217.
21. Walcher L, Kistenmacher AK, Suo H, et al. Cancer stem cells-origins and biomarkers: Perspectives for targeted personalized therapies. Front Immunol, 2020, 11: 1280.
22. Heng WS, Gosens R, Kruyt FAE. Lung cancer stem cells: Origin, features, maintenance mechanisms and therapeutic targeting. Biochem Pharmacol, 2019, 160: 121-133.
23. Pereira CV, Duarte M, Silva P, et al. Polymethoxylated flavones target cancer stemness and improve the antiproliferative effect of 5-fluorouracil in a 3D cell model of colorectal cancer. Nutrients, 2019, 11(2): 326.
24. Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther, 2020, 5(1): 8.
25. Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A, 2009, 106(1): 268-273.
26. Huang EH, Hynes MJ, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res, 2009, 69(8): 3382-3389.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Tangeretin inhibits tumor stemness of non-small cell lung cancer by regulating PI3K/AKT/mTOR signaling pathway

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