Abstract: Metabolic reprogramming is a common phenomenon in cancer, with aerobic glycolysis being one of its important characteristics. Hypoxia-inducible factor-1α (HIF1Α) is thought to play an important role in aerobic glycolysis. Meanwhile, naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits. In this work, we identified glycolytic genes related to HIF1Α by analyzing the colon cancer database. The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Α overexpression on glycolysis, and the proliferation and migration of colon cancer cells. Moreover, naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Α function. The results showed that the HIF1Α and enolase 2 (ENO2) levels in colon cancer tissues were highly correlated, and their high expression indicated a poor prognosis for colon cancer patients. Mechanistically, HIF1Α directly binds to the DNA promoter region and upregulates the transcription of ENO2; ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells. Most importantly, we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α, which in turn decreased aerobic glycolysis in colon cancer cells. Generally, naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Α and the proliferation and invasion of colon cancer cells. This study helps to elucidate the relationship between colon cancer progression and glucose metabolism, and demonstrates the efficacy of naringin in the treatment of colon cancer.

柚皮苷通过HIF1A通路抑制结肠癌的有氧糖酵解

[1]AdemosunAO, ObohG, PassamontiS, et al., 2015. Inhibition of metalloproteinase and proteasome activities in colon cancer cells by citrus peel extracts. J Basic Clin Physiol Pharmacol, 26(5):471-477.

[2]AhmadSS, GlatzleJ, BajaeiferK, et al., 2013. Phosphoglycerate kinase 1 as a promoter of metastasis in colon cancer. Int J Oncol, 43(2):586-590.

[3]AndréT, de GramontA, VernereyD, et al., 2015. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol, 33(35):4176-4187.

[4]AndreouD, SteenNE, JørgensenKN, et al., 2021. Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness. Psychol Med, published online.

[5]AnsariB, AschnerM, HussainY, et al., 2022. Suppression of colorectal carcinogenesis by naringin. Phytomedicine, 96:153897.

[6]CartwrightTH, 2012. Treatment decisions after diagnosis of metastatic colorectal cancer. Clin Colorectal Cancer, 11(3):155-166.

[7]ChenR, QiQL, WangMT, et al., 2016. Therapeutic potential of naringin: an overview. Pharm Biol, 54(12):3203-3210.

[8]DenlingerCS, BarsevickAM, 2009. The challenges of colorectal cancer survivorship. J Natl Compr Canc Netw, 7(8):883-894.

[9]DienstmannR, SalazarR, TaberneroJ, 2015. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol, 33(16):1787-1796.

[10]DuX, ZhangJ, LiuL, et al., 2022. A novel anticancer property of Lycium barbarum polysaccharide in triggering ferroptosis of breast cancer cells. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(4):286-299.

[11]GopinathK, SudhandiranG, 2012. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience, 227:134-143.

[12]HabauzitV, SaccoSM, Gil-IzquierdoA, et al., 2011. Differential effects of two citrus flavanones on bone quality in senescent male rats in relation to their bioavailability and metabolism. Bone, 49(5):1108-1116.

[13]HsuPP, SabatiniDM, 2008. Cancer cell metabolism: Warburg and beyond. Cell, 134(5):703-707.

[14]HuHL, ZhuWW, QinJ, et al., 2017. Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology, 65(2):515-528.

[15]JiangXY, ChenZ, ZhuJP, et al., 2022. E2F1 promotes Warburg effect and cancer progression via upregulating ENO2 expression in Ewing sarcoma. Mol Med Rep, 26(1):237.

[16]KimDI, LeeSJ, LeeSB, et al., 2008. Requirement for Ras/Raf/ERK pathway in naringin-induced G₁-cell-cycle arrest via p21WAF1 expression. Carcinogenesis, 29(9):‍1701-1709.

[17]KimJ, JinH, ZhaoJC, et al., 2017. FOXA1 inhibits prostate cancer neuroendocrine differentiation. Oncogene, 36(28):4072-4080.

[18]KimJW, DangCV, 2005. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci, 30(3):142-150.

[19]KoppenolWH, BoundsPL, DangCV, 2011. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer, 11(5):325-337.

[20]LiHZ, YangB, HuangJ, et al., 2013. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β‍-catenin signaling pathway. Toxicol Lett, 220(3):219-228.

[21]LiuDS, MaoYM, ChenC, et al., 2020. Expression patterns and clinical significances of ENO2 in lung cancer: an analysis based on Oncomine database. Ann Transl Med, 8(10):639.

[22]LuoYL, ZhangCC, LiPB, et al., 2012. Naringin attenuates enhanced cough, airway hyperresponsiveness and airway inflammation in a guinea pig model of chronic bronchitis induced by cigarette smoke. Int Immunopharmacol, 13(3):301-307.

[23]MillerKD, NogueiraL, MariottoAB, et al., 2019. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin, 69(5):363-385.

[24]RajedadramA, PinKY, LingSK, et al., 2021. Hydroxychavicol, a polyphenol from Piper betle leaf extract, induces cell cycle arrest and apoptosis in TP53-resistant HT-29 colon cancer cells. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(2):112-122.

[25]RamzyA, ElSafyS, ElshokyHA, et al., 2023. Drugless nanoparticles tune-up an array of intertwined pathways contributing to immune checkpoint signaling and metabolic reprogramming in triple-negative breast cancer. Biomed Mater, 18:015023.

[26]SchwartzL, SeyfriedT, AlfaroukKO, et al., 2017. Out of Warburg effect: an effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol, 43:134-138.

[27]SohMA, GarrettSH, SomjiS, et al., 2011. Arsenic, cadmium and neuron specific enolase (ENO2, γ‍-enolase) expression in breast cancer. Cancer Cell Int, 11:41.

[28]SunBY, LiuYQ, HeDH, et al., 2021. Traditional Chinese medicines and their active ingredients sensitize cancer cells to TRAIL-induced apoptosis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(3):190-203.

[29]TaiebJ, le MalicotK, ShiQ, et al., 2017. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst, 109(5):djw272.

[30]VanamalaJ, LeonardiT, PatilBS, et al., 2006. Suppression of colon carcinogenesis by bioactive compounds in grapefruit. Carcinogenesis, 27(6):1257-1265.

[31]vander HeidenMG, CantleyLC, ThompsonCB, 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930):1029-1033.

[32]WangDM, YanJQ, ChenJ, et al., 2015. Naringin improves neuronal insulin signaling, brain mitochondrial function, and cognitive function in high-fat diet-induced obese mice. Cell Mol Neurobiol, 35(7):1061-1071.

[33]WarburgO, WindF, NegeleinE, 1927. The metabolism of tumors in the body. J Gen Physiol, 8(6):519-530.

[34]YuLL, LuMY, JiaDY, et al., 2017. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res, 77(7):1564-1574.

[35]YukimotoR, NishidaN, HataT, et al., 2021. Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer. Cancer Sci, 112(7):2884-2894.

[36]ZhangJZ, GaoWY, LiuZ, et al., 2014. Systematic analysis of main constituents in rat biological samples after oral administration of the methanol extract of fructus aurantii by HPLC-ESI-MS/MS. Iran J Pharm Res, 13(2):493503.

[37]ZhengY, WuC, YangJM, et al., 2020. Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer. Sig Transduct Target Ther, 5:53.