Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis

doi:10.1007/s11306-022-01968-7

. 2023 Jan 16;19(2):6.

doi: 10.1007/s11306-022-01968-7.

Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis

Rong Zhang^#^{1

2}, Zijia Zhang^#^{1

2}, Wenyong Wu^{1

2

3}, Jingying Shi^{1

2}, Entezar Berk^{1

2

4}, Wei Li^{1

2}, Yanping Deng^{1

2}, Zhaojun Wang^{1

2}, Jinjun Hou^{1

2}, Huali Long^{1

2}, Min Lei^{5

6}, Wanying Wu^{7

8}

Affiliations

¹ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
² University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China.
⁴ Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
⁵ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. mlei@simm.ac.cn.
⁶ University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. mlei@simm.ac.cn.
⁷ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. wanyingwu@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. wanyingwu@simm.ac.cn.

^# Contributed equally.

PMID: 36645548
DOI: 10.1007/s11306-022-01968-7

Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis

Rong Zhang et al. Metabolomics. 2023.

. 2023 Jan 16;19(2):6.

doi: 10.1007/s11306-022-01968-7.

Authors

Affiliations

¹ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
² University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China.
⁴ Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
⁵ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. mlei@simm.ac.cn.
⁶ University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. mlei@simm.ac.cn.
⁷ Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China. wanyingwu@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. wanyingwu@simm.ac.cn.

^# Contributed equally.

PMID: 36645548
DOI: 10.1007/s11306-022-01968-7

Abstract

Introduction: Lipid metabolism participates in various biological processes such as proliferation, apoptosis, migration, invasion, and maintenance of membrane homeostasis of prostate tumor cells. Bufadienolides, the active ingredients of Chansu, show a robust anti-proliferative effect against prostate cancer cells in vitro, but whether bufadienolides could regulate the lipid metabolism in prostate cancer has not been evaluated.

Objectives: Our study explored the regulatory effects of bufadienolides on lipid metabolism in human prostate carcinoma cells (PC-3).

Methods: Untargeted lipidomics and transcriptomics were combined to study the effect of different bufadienolides interventions on lipid and gene changes of PC-3 cells. The key genes related to lipid metabolism and prostate cancer development were verified by qPCR and western blotting.

Results: Lipidomic analysis showed that the active bufadienolides significantly downregulated the content of long-chain lipids of PC-3 cells. Based on transcriptomic and qPCR analyses, many genes related to lipid metabolism were significantly regulated by active bufadienolides, such as ELOVL6, CYP2E1, GAL3ST1, CERS1, PLA2G10, PLD1, SPTLC3, and GPX2. Bioinformatics analysis of the Cancer Genome Atlas database and literature retrieval showed that elongation of very long-chain fatty acids protein 6 (ELOVL6) and phospholipase D1 (PLD1) might be important regulatory genes. Western blot analysis revealed that active bufadienolides could downregulate PLD1 protein levels which might promote anti-prostate cancer effect.

Conclusions: All these findings support that bufadienolides might induce lipid metabolic remodeling by regulating long-chain lipids synthesis and phospholipid hydrolysis to achieve an anti-prostate cancer effect, and PLD1 would probably be the key protein.

Keywords: Bufadienolides; ELOVL6; Lipidomics; PLD1; Prostate cancer; Transcriptomics.

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TransGEM: a molecule generation model based on Transformer with gene expression data.
Liu Y, Yu H, Duan X, Zhang X, Cheng T, Jiang F, Tang H, Ruan Y, Zhang M, Zhang H, Zhang Q. Liu Y, et al. Bioinformatics. 2024 May 2;40(5):btae189. doi: 10.1093/bioinformatics/btae189. Bioinformatics. 2024. PMID: 38632084 Free PMC article.

References

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1. Berger, A. C., Korkut, A., Kanchi, R. S., Hegde, A. M., Lenoir, W., Liu, W., Liu, Y., Fan, H., Shen, H., Ravikumar, V., Rao, A., Schultz, A., Li, X., Sumazin, P., Williams, C., Mestdagh, P., Gunaratne, P. H., Yau, C., Bowlby, R., et al. (2018). A Comprehensive pan-cancer molecular study of gynecologic and breast cancers. Cancer Cell, 33(4), 690–705. https://doi.org/10.1016/j.ccell.2018.03.014 - DOI - PubMed - PMC
1. Bowling, F. Z., Salazar, C. M., Bell, J. A., Huq, T. S., Frohman, M. A., & Airola, M. V. (2020). Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA. Nature Chemical Biology, 16(4), 400–407. https://doi.org/10.1038/s41589-020-0499-8 - DOI - PubMed - PMC
1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.21492 - DOI - PubMed
1. Brigelius-Flohe, R., & Flohe, L. (2020). Regulatory Phenomena in the Glutathione Peroxidase Superfamily. Antioxidants & Redox Signaling, 33(7), 498–516. https://doi.org/10.1089/ars.2019.7905 - DOI

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[1] Attard, G., Parker, C., Eeles, R. A., Schröder, F., Tomlins, S. A., Tannock, I., Drake, C. G., & de Bono, J. S. (2016). Prostate cancer. The Lancet, 387(10013), 70–82. https://doi.org/10.1016/s0140-6736(14)61947-4 - DOI

[2] Attard, G., Parker, C., Eeles, R. A., Schröder, F., Tomlins, S. A., Tannock, I., Drake, C. G., & de Bono, J. S. (2016). Prostate cancer. The Lancet, 387(10013), 70–82. https://doi.org/10.1016/s0140-6736(14)61947-4 - DOI

[3] Berger, A. C., Korkut, A., Kanchi, R. S., Hegde, A. M., Lenoir, W., Liu, W., Liu, Y., Fan, H., Shen, H., Ravikumar, V., Rao, A., Schultz, A., Li, X., Sumazin, P., Williams, C., Mestdagh, P., Gunaratne, P. H., Yau, C., Bowlby, R., et al. (2018). A Comprehensive pan-cancer molecular study of gynecologic and breast cancers. Cancer Cell, 33(4), 690–705. https://doi.org/10.1016/j.ccell.2018.03.014 - DOI - PubMed - PMC

[4] Berger, A. C., Korkut, A., Kanchi, R. S., Hegde, A. M., Lenoir, W., Liu, W., Liu, Y., Fan, H., Shen, H., Ravikumar, V., Rao, A., Schultz, A., Li, X., Sumazin, P., Williams, C., Mestdagh, P., Gunaratne, P. H., Yau, C., Bowlby, R., et al. (2018). A Comprehensive pan-cancer molecular study of gynecologic and breast cancers. Cancer Cell, 33(4), 690–705. https://doi.org/10.1016/j.ccell.2018.03.014 - DOI - PubMed - PMC

[5] Bowling, F. Z., Salazar, C. M., Bell, J. A., Huq, T. S., Frohman, M. A., & Airola, M. V. (2020). Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA. Nature Chemical Biology, 16(4), 400–407. https://doi.org/10.1038/s41589-020-0499-8 - DOI - PubMed - PMC

[6] Bowling, F. Z., Salazar, C. M., Bell, J. A., Huq, T. S., Frohman, M. A., & Airola, M. V. (2020). Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA. Nature Chemical Biology, 16(4), 400–407. https://doi.org/10.1038/s41589-020-0499-8 - DOI - PubMed - PMC

[7] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.21492 - DOI - PubMed

[8] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.21492 - DOI - PubMed

[9] Brigelius-Flohe, R., & Flohe, L. (2020). Regulatory Phenomena in the Glutathione Peroxidase Superfamily. Antioxidants & Redox Signaling, 33(7), 498–516. https://doi.org/10.1089/ars.2019.7905 - DOI

[10] Brigelius-Flohe, R., & Flohe, L. (2020). Regulatory Phenomena in the Glutathione Peroxidase Superfamily. Antioxidants & Redox Signaling, 33(7), 498–516. https://doi.org/10.1089/ars.2019.7905 - DOI

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Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis

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Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis

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