Anthocyanins prevent the development and progression of urethane-induced lung cancer by regulating energy metabolism in mice

Han Luo; Mengyuan Gao; Hong Lu; Qianyao Chen; Xuemei Lian

doi:10.29219/fnr.v68.10434

Han Luo Department of Nutrition and Food Hygiene, School of Public Health, Chongqing Medical University
Mengyuan Gao Department of Nutrition and Food Hygiene, School of Public Health, Chongqing Medical University
Hong Lu Department of Nutrition and Food Hygiene, School of Public Health, Chongqing Medical University
Qianyao Chen Department of Nutrition and Food Hygiene, School of Public Health, Chongqing Medical University
Xuemei Lian Chongqing Medical University

DOI: https://doi.org/10.29219/fnr.v68.10434

Keywords: anthocyanin, lung cancer, energy metabolism

Abstract

Anthocyanin (ACN) is a natural antioxidant with multiple biological activities, and the aim of this study was to evaluate the protective effect of ACN on the development and progression of lung cancer and to further explore its possible mechanism of action. In vivo, we fed C57BL/6J mice a 0.5%ACN diet or a control diet to observe their effects on the development and progression of urethane-induced lung cancer. In vitro, multiple lung cancer cell lines were used to investigate the effects of C3G on cell viability. The results showed a reduction in lung tumor burden and downregulation of oxidative phosphorylation and fatty acid degradation pathways in lung tissue of urethane-administrated ACN-fed mice compared with control diet-fed mice. In vitro, cyanidin-3-O-glucoside chloride (C3G) intervention treatment significantly inhibited proliferation and apoptosis of A549 cells. This process is likely due to the modulation of AMPK/mTOR signaling pathway by C3G to regulate cellular fatty acid metabolism and reduce intracellular lipid accumulation which affects the growth of lung cancer cells. These results suggest that ACN can inhibit the development and progression of urethane-induced lung tumors and alter the lipid metabolism of tumors in C57BL/6J mice.

Downloads

Download data is not yet available.

References

1.
Sung H, Ferlay, J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–49. doi: 10.3322/caac.21660

2.
Thunnissen E, Witte BI, Aisner S, Beasley MB, Brambilla E, Chirieac LR, et al. Reproducibility of histopathological diagnosis in poorly differentiated NSCLC: an international multiobserver study. J Thorac Oncol 2015; 10: e4. doi: 10.1097/JTO.0000000000000425

3.
Safdar, MA, Aslam, RMN, Shakeel A, Shiza, Waqar M, Jmail A, et al. Cyanidin as potential anticancer agent targeting various proliferative pathways. Chem Biol Drug Design 2022; 101: 438–52. doi: 10.1111/cbdd.14173

4.
Polański J, Świątoniowska-Lonc N, Kołaczyńska S, Chabowski M. Diet as a Factor Supporting Lung Cancer Treatment-A Systematic Review. Nutrients. 2023;15(6):1477. doi: 10.3390/nu150

5.
Ding M, Feng R, Wang SY, Bowman L, Lu Y, Qian Y, et al. Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity. J Biol Chem 2006; 281: 17359–68. doi: 10.1074/jbc.M600861200

6.
Zheng J, Zhou Y, Li Y, Xu DP, Li S, Li HB. Spices for Prevention and Treatment of Cancers. Nutrients. 2016;8(8):495. doi: 10.3390/nu8080495

7.
Zhou Y, Zheng J, Li Y, et al. Natural Polyphenols for Prevention and Treatment of Cancer. Nutrients. 2016;8(8):515. doi: 10.3390/nu8080515

8.
Farvid MS, Chen WY, Michels KB, Cho E, Willett WC, Eliassen AH. Fruit and vegetable consumption in adolescence and early adulthood and risk of breast cancer: population based cohort study. BMJ. 2016;353:i2343. doi: 10.1136/bmj.i2343

9.
Zhou Y, Li Y, Zhou T, Zheng J, Li S, Li HB. Dietary Natural Products for Prevention and Treatment of Liver Cancer. Nutrients. 2016;8(3):156. doi: 10.3390/nu8030156

10.
Li Y, Li S, Meng X, Gan RY, Zhang JJ, Li HB. Dietary Natural Products for Prevention and Treatment of Breast Cancer. Nutrients. 2017;9(7):728. doi: 10.3390/nu9070728

11.
Riaz M, Zia-Ul-Haq M, Saad B. Springer briefs in food, health, and nutrition. Cham: Springer; 2016, pp. XII, 138.

12.
Kong JM, Chia LS, Goh NK, Chia TF, Brouillard R. Analysis and biological activities of anthocyanins. Phytochemistry 2003; 64: 923–33. doi: 10.1016/s0031-9422(03)00438-2

13.
Wallace TC, Giusti MM. Anthocyanins. Adv Nutr 2015; 6: 620–2. doi: 10.3945/an.115.009233

14.
Guo Y, Zhang P, Liu Y, Zha L, Ling W, Guo H. A dose-response evaluation of purified anthocyanins on inflammatory and oxidative biomarkers and metabolic risk factors in healthy young adults: a randomized controlled trial. Nutrition 2020; 74: 110745. doi: 10.1016/j.nut.2020.110745

15.
Hu X, Yang Y, Tang S, et al. Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. Int J Mol Sci. 2023;24(2):1528. doi: 10.3390/ijms24021528

16.
Wang D, Zou T, Yang Y, Yan X, Ling W. Cyanidin-3-O-beta-glucoside with the aid of its metabolite protocatechuic acid, reduces monocyte infiltration in apolipoprotein E-deficient mice. Biochem Pharmacol 2011; 82: 713–9. doi: 10.1016/j.bcp.2011.04.007

17.
Bars-Cortina D, Sakhawat A, Pinol-Felis C, Motilva MJ. Chemopreventive effects of anthocyanins on colorectal and breast cancer: a review. Semin Cancer Biol 2022; 81: 241–58. doi: 10.1016/j.semcancer.2020.12.013

18.
Chen PN, Chu SC, Chiou HL, Chiang CL, Yang SF, Hsieh YS. Cyanidin 3-glucoside and Peonidin 3-glucoside inhibit tumor cell growth and induce apoptosis in vitro and suppress tumor growth in vivo. Nutr Cancer 2005; 53: 232–43. doi: 10.1207/s15327914nc5302_12

19.
Mohammed HA, Khan RA. Anthocyanins: traditional uses, structural and functional variations, approaches to increase yields and products’ quality, hepatoprotection, liver longevity, and commercial products. Int J Mol Sci 2022; 23. doi: 10.3390/ijms23042149

20.
Sajadimajd S, Bahramsoltani R, Iranpanah A, Kumar Patra J, Das G, Gouda S, et al. Advances on natural polyphenols as anticancer agents for skin cancer. Pharmacol Res 2020; 151: 104584. doi: 10.1016/j.phrs.2019.104584

21.
Zhang Y, Zhu M, Wan H, Chen L, Luo F. Association between Dietary Anthocyanidins and Risk of Lung Cancer. Nutrients. 2022;14(13):2643. doi: 10.3390/nu14132643

22.
Currie E, Schulze A, Zechner R, Walther TC, Farese Jr, RV. Cellular fatty acid metabolism and cancer. Cell Metab 2013; 18: 153–61. doi: 10.1016/j.cmet.2013.05.017

23.
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007; 7: 763–77. doi: 10.1038/nrc2222

24.
Gouw AM, Eberlin LS, Margulis K, Sullivan DK, Toal GG, Tong L, et al. Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc Natl Acad Sci U S A 2017; 114: 4300–5. doi: 10.1073/pnas.1617709114

25.
Madak-Erdogan Z, Band S, Zhao YC, Smith BP, Kulkoyluoglu-Cotul E, Zuo Q, et al. Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling. Cancer Res 2019; 79: 2494–510. doi: 10.1158/0008-5472.Can-18-2849

26.
Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer 2019; 122: 4–22. doi: 10.1038/s41416-019-0650-z

27.
Miller YE, Dwyer-Nield LD, Keith RL, Le M, Franklin WA, Malkinson AM. Induction of a high incidence of lung tumors in C57BL/6 mice with multiple ethyl carbamate injections. Cancer Lett 2003; 198: 139–44. doi: 10.1016/s0304-3835(03)00309-4

28.
Chen SF, Zhou YQ, Chen YR, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 2018; 34(17): i884–90. doi: 10.1093/bioinformatics/bty560

29.
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods 2015; 12: 357–60. doi: 10.1038/nmeth.3317

30.
Roberts A, Trapnell C, Donaghey J, Rinn JL, Pachter L. Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol 2011; 12(3): R22. doi: 10.1186/gb-2011-12-3-r22

31.
Anders S, Pyl PT, Huber W. HTSeq – a Python framework to work with high-throughput sequencing data. Bioinformatics 2015; 31: 166–9. doi: 10.1093/bioinformatics/btu638

32.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15: 550. doi: 10.1186/s13059-014-0550-8

33.
Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res 2008; 36: D480–4. doi: 10.1093/nar/gkm882

34.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102: 15545–50. doi: 10.1073/pnas.0506580102

35.
Wu T, Gao Y, Guo X, Zhang M, Gong L. Blackberry and blueberry anthocyanin supplementation counteract high-fat-diet-induced obesity by alleviating oxidative stress and inflammation and accelerating energy expenditure. Oxid Med Cell Longev 2018; 2018: 4051232. doi: 10.1155/2018/4051232

36.
Martinez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer 2021; 21: 669–80. doi: 10.1038/s41568-021-00378-6

37.
Kausar H, Jeyabalan J, Aqil F, Chabba D, Sidana J, Singh IP, et al. Berry anthocyanidins synergistically suppress growth and invasive potential of human non-small-cell lung cancer cells. Cancer Lett 2012; 325: 54–62. doi: 10.1016/j.canlet.2012.05.029

38.
Wu CF, Wu CY, Lin CF, Liu YW, Lin TC, Liao HJ, et al. The anticancer effects of cyanidin 3-O-glucoside combined with 5-fluorouracil on lung large-cell carcinoma in nude mice. Biomed Pharmacother 2022; 151: 113128. doi: 10.1016/j.biopha.2022.113128

39.
Chen X, Zhang W, Xu X. Cyanidin-3-glucoside suppresses the progression of lung adenocarcinoma by downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway. World J Surg Oncol 2021; 19: 232. doi: 10.1186/s12957-021-02339-7

40.
Pal HC, Sharma S, Strickland LR, Agarwal J, Athar M, Elmets CA, et al. Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways. PLoS One 2013; 8: e77270. doi: 10.1371/journal.pone.0077270

41.
Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007; 8: 774–85. doi: 10.1038/nrm2249

42.
Gonzalez A, Hall MN. Nutrient sensing and TOR signaling in yeast and mammals. EMBO J 2017; 36: 397–408. doi: 10.15252/embj.201696010

43.
Xu J, Ji J, Yan XH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 2012; 52: 373–81. doi: 10.1080/10408398.2010.500245

44.
Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 2016; 22: 1108–19. doi: 10.1038/nm.4181

45.
Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer 2018; 18: 744–57. doi: 10.1038/s41568-018-0074-8

46.
Peterson, Timothy R, Sengupta, Shomit S, Harris, Thurl E, Carmack, Anne E, Kang, Seong A, Balderas E, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146: 408–20. doi: 10.1016/j.cell.2011.06.034

47.
Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk. Cell 2005; 121: 179–93. doi: 10.1016/j.cell.2005.02.031

48.
Christofides A, Konstantinidou E, Jani C, Boussiotis VA. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism. 2021;114:154338. doi: 10.1016/j.metabol.2020.154338

49.
Tang Z, Shen Q, Xie H, Zhou XY, Li J, Feng J, et al. Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC). Oncotarget 2016; 7(29): 46253–62. doi: 10.18632/oncotarget.10086

50.
Li F, Gu Y, Dong W, Li H, Zhang L, Li N, et al. Cell death-inducing DFF45-like effector, a lipid droplet-associated protein, might be involved in the differentiation of human adipocytes. FEBS J 2010; 277: 4173–83. doi: 10.1111/j.1742-4658.2010.07806.x

51.
Kim JY, Liu K, Zhou S, Tillison K, Wu Y, Smas CM. Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death. Am J Physiol Endocrinol Metab 2008; 294: E654–67. doi: 10.1152/ajpendo.00104.2007