Curcumin inhibits lipid metabolism in non-small cell lung cancer by downregulating the HIF-1α pathway

doi:10.12122/j.issn.1673-4254.2025.05.17

Abstract

Abstract:

Objective To investigate the effect of curcumin on lipid metabolism in non-small cell lung cancer (NSCLC) and its molecular mechanism. Methods The inhibitory effect of curcumin (0-70 μmol/L) on proliferation of A549 and H1299 cells was assessed using MTT assay, and 20 and 40 μmol/L curcumin was used in the subsequent experiments. The effect of curcumin on lipid metabolism was evaluated using cellular uptake assay, wound healing assay, triglyceride (TG)/free fatty acid (NEFA) measurements, and Oil Red O staining. Western blotting was performed to detect the expressions of PGC-1α, PPAR-α, and HIF-1α in curcumin-treated cells. Network pharmacology was used to predict the metabolic pathways, and the results were validated by Western blotting. In a nude mouse model bearing A549 cell xenograft, the effects of curcumin (20 mg/kg) on tumor growth and lipid metabolism were assessed by measuring tumor weight and observing the changes in intracellular lipid droplets. Results Curcumin concentration-dependently inhibited the proliferation of A549 and H1299 cells and significantly reduced TG and NEFA levels and intracellular lipid droplets. Western blotting revealed that curcumin significantly upregulated PGC-1α and PPAR‑α expressions in the cells. KEGG pathway enrichment analysis predicted significant involvement of the HIF-1 signaling pathway in curcumin-treated NSCLC, suggesting a potential interaction between HIF-1α and PPAR‑α. Western blotting confirmed that curcumin downregulated the expression of HIF-1α. In the tumor-bearing mice, curcumin treatment caused significant reduction of the tumor weight and the number of lipid droplets in the tumor cells. Conclusion Curcumin inhibits NSCLC cell proliferation and lipid metabolism by downregulating the HIF-1α pathway.

Key words: curcumin, non-small cell lung cancer, lipid metabolism, HIF-1α pathway

Dandan LI, Jiaxin CHU, Yan YAN, Wenjun XU, Xingchun ZHU, Yun SUN, Haofeng DING, Li REN, Bo ZHU. Curcumin inhibits lipid metabolism in non-small cell lung cancer by downregulating the HIF-1α pathway[J]. Journal of Southern Medical University, 2025, 45(5): 1039-1046.

Figures/Tables 7

Fig.1 Inhibitory effect of curcumin on proliferation of A549 and H1299 cells. A, B: Effect of curcumin on viability of A549 and H1299 cells. C, D: Wound healing assay of curcumin-treated A549 and H1299 cells. *P<0.05 vs Curcumin 0; #P<0.05 vs Curcumin 20..

Fig.2 The ability of A549 and H1299 cells to take up Curcumin.

Fig.3 Effect of curcumin on lipid metabolism in A549 and H1299 cells. A: Curcumin lowers TG content in A549 and H1299 cells. B: Curcumin lowers NEFA content in A549 and H1299 cells. C: Curcumin reduces lipid drops in A549 and H1299 cells. *P<0.05 vs Curcumin 0; #P<0.05 vs Curcumin 20.

Fig.4 Effect of curcumin on PPAR-α and PGC-1α protein expression detected by Western blotting. *P<0.05 vs Curcumin 0; #P<0.05 vs Curcumin 20.

Fig.5 Results of network pharmacological analysis. A: Venn diagram of NSCLC gene-curcumin target genes. B: PPI network diagram of NSCLC gene-curcumin target genes. C: KEGG enriched pathways for the intersection targets of NSCLC and Curcumin. D: PPI network diagram of adipogenesis.

Fig.6 Effect of curcumin on HIF-1α protein expression in A549 and H1299 cells. *P<0.05 vs Curcumin 0. #P<0.05 vs Curcumin 20.

Fig.7 Effect of curcumin on growth of A549 xenografts in nude mice. A, B: Changes in tumor weight in the nude mice. C: Effect of curcumin on lipid droplets in the tumor cells. *P<0.05 vs Control.

References 35

1	Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J]. CA A Cancer J Clinicians, 2023, 73(1): 17-48.
2	Chen PX, Liu YH, Wen YK, et al. Non-small cell lung cancer in China[J]. Cancer Commun, 2022, 42(10): 937-70.
3	Bian X, Liu R, Meng Y, et al. Lipid metabolism and cancer[J]. J Exp Med, 2021, 218(1).
4	Yin Y, He MQ, Huang YJ, et al. Transcriptomic analysis identifies CYP27A1 as a diagnostic marker for the prognosis and immunity in lung adenocarcinoma[J]. BMC Immunol, 2023, 24(1): 37.
5	Quispe C, Herrera-Bravo J, Javed Z, et al. Therapeutic applications of curcumin in diabetes: a review and perspective[J]. Biomed Res Int, 2022, 2022: 1375892.
6	Li XS, Zhu RG, Jiang H, et al. Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis[J]. Acta Pharm Sin B, 2022, 12(5): 2280-99.
7	Tang CY, Liu JT, Yang CS, et al. Curcumin and its analogs in non-small cell lung cancer treatment: challenges and expectations[J]. Biomolecules, 2022, 12(11): 1636.
8	Ming TQ, Tao Q, Tang S, et al. Curcumin: an epigenetic regulator and its application in cancer[J]. Biomed Pharmacother, 2022, 156: 113956.
9	Ashrafizadeh M, Najafi M, Makvandi P, et al. Versatile role of curcumin and its derivatives in lung cancer therapy[J]. J Cell Physiol, 2020, 235(12): 9241-68.
10	Shan DD, Wang JM, Di QN, et al. Steatosis induced by nonylphenol in HepG2 cells and the intervention effect of curcumin[J]. Food Funct, 2022, 13(1): 327-43.
11	Wu SF, Kong XF, Sun Y, et al. FABP3 overexpression promotes vascular fibrosis in Takayasu's arteritis by enhancing fatty acid oxidation in aorta adventitial fibroblasts[J]. Rheumatology, 2022, 61(7): 3071-81.
12	Li RQ, Li XQ, Zhao J, et al. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation[J]. Theranostics, 2022, 12(2): 976-98.
13	Nosrati-Oskouie M, Aghili-Moghaddam NS, Sathyapalan T, et al. Impact of curcumin on fatty acid metabolism[J]. Phytother Res, 2021, 35(9): 4748-62.
14	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-49.
15	Li MJ, Guo TT, Lin JY, et al. Curcumin inhibits the invasion and metastasis of triple negative breast cancer via Hedgehog/Gli1 signaling pathway[J]. J Ethnopharmacol, 2022, 283: 114689.
16	Liu CF, Rokavec M, Huang ZK, et al. Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis[J]. Cell Death Differ, 2023, 30(7): 1771-85.
17	Li JT, Wei HL, Liu YG, et al. Curcumin inhibits hepatocellular carcinoma via regulating miR-21/TIMP3 axis[J]. Evid Based Complement Alternat Med, 2020, 2020: 2892917.
18	Bahrami A, Ferns GA. Effect of curcumin and its derivates on gastric cancer: molecular mechanisms[J]. Nutr Cancer, 2021, 73(9): 1553-69.
19	Guariglia M, Saba F, Rosso C, et al. Molecular mechanisms of curcumin in the pathogenesis of metabolic dysfunction associated steatotic liver disease[J]. Nutrients, 2023, 15(24): 5053.
20	Lee SC, Jee SC, Kim M, et al. Curcumin suppresses the lipid accumulation and oxidative stress induced by benzo [a] Pyrene toxicity in HepG2 cells[J]. Antioxidants, 2021, 10(8): 1314.
21	Ceja-Galicia ZA, García-Arroyo FE, Aparicio-Trejo OE, et al. Therapeutic effect of curcumin on 5/6Nx hypertriglyceridemia: association with the improvement of renal mitochondrial β‑oxidation and lipid metabolism in kidney and liver[J]. Antioxidants, 2022, 11(11): 2195.
22	Sun T, Chen JG, Yang F, et al. Lipidomics reveals new lipid-based lung adenocarcinoma early diagnosis model[J]. EMBO Mol Med, 2024, 16(4): 854-69.
23	Schlaepfer IR, Joshi M. CPT1A-mediated fat oxidation, mechan-isms, and therapeutic potential[J]. Endocrinology, 2020, 161(2): bqz046.
24	Eltayeb K, Monica SL, Tiseo M, et al. Reprogramming of lipid metabolism in lung cancer: an overview with focus on EGFR-mutated non-small cell lung cancer[J]. Cells, 2022, 11(3): 413.
25	Ni HY, Yu L, Zhao XL, et al. Seed oil of Rosa roxburghii Tratt against non-alcoholic fatty liver disease in vivo and in vitro through PPARα/PGC-1α-mediated mitochondrial oxidative metabolism[J]. Phytomedicine, 2022, 98: 153919.
26	Zhou S, Ling X, Liang Y, et al. Cannabinoid receptor 2 plays a key role in renal fibrosis through inhibiting lipid metabolism in renal tubular cells[J]. Metabolism, 2024, 159: 155978.
27	Li DD, Ma JM, Li MJ, et al. Supplementation of Lycium barbarum polysaccharide combined with aerobic exercise ameliorates high-fat-induced nonalcoholic steatohepatitis via AMPK/PPARα/PGC-1α pathway[J]. Nutrients, 2022, 14(15): 3247.
28	Infantino V, Santarsiero A, Convertini P, et al. Cancer cell metabolism in hypoxia: role of HIF-1 as key regulator and therapeutic target[J]. Int J Mol Sci, 2021, 22(11): 5703.
29	Luo F, Lu FT, Cao JX, et al. HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer[J]. Cancer Lett, 2022, 531: 39-56.
30	Wu H, Zhao XF, Hochrein SM, et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α‑mediated glycolytic reprogramming[J]. Nat Commun, 2023, 14(1): 6858.
31	Kierans SJ, Fagundes RR, Malkov MI, et al. Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression[J]. Proc Natl Acad Sci USA, 2023, 120(35): e2208117120.
32	Mylonis I, Simos G, Paraskeva E. Hypoxia-inducible factors and the regulation of lipid metabolism[J]. Cells, 2019, 8(3): 214.
33	Chen Y, Xu X, Wang YR, et al. Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation[J]. J Exp Clin Cancer Res, 2023, 42(1): 265.
34	Huang CY, Yong QH, Lu YH, et al. Gentiopicroside improves non-alcoholic steatohepatitis by activating PPARα and suppressing HIF1[J]. Front Pharmacol, 2024, 15: 1335814.
35	Li YY, Lu Y, Lin SH, et al. Insulin signaling establishes a developmental trajectory of adipose regulatory T cells[J]. Nat Immunol, 2021, 22(9): 1175-85.

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