Multi-omics Analysis Revealed the Mitochondrial-targeted Drug Combination to Suppress the Development of Lung Cancer

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2023 Oct 2

PMID 37783930

Authors

Chaoqun Li

Yanfei Zhang

Qing Xia

Bingjie Hao

Yifan Hong

Liduo Yue

Tiansheng Zheng

Ming Li

Lihong Fan

Affiliations

Soon will be listed here.

Abstract

Purpose: The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies.

Methods: In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets.

Results: We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics.

Conclusions: Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs.

Citing Articles

Proteomic changes orchestrate metabolic acclimation of a unicellular diazotrophic cyanobacterium during light-dark cycle and nitrogen fixation states.

Panda P, Giri S, Sherman L, Kihara D, Aryal U bioRxiv. 2024; .

PMID: 39131303 PMC: 11312527. DOI: 10.1101/2024.07.30.605809.

References

Ahn C, Metallo C . Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 2015; 3(1):1. PMC: 4305394. DOI: 10.1186/s40170-015-0128-2. View

Anderson R, Ghiraldeli L, Pardee T . Mitochondria in cancer metabolism, an organelle whose time has come?. Biochim Biophys Acta Rev Cancer. 2018; 1870(1):96-102. PMC: 6420819. DOI: 10.1016/j.bbcan.2018.05.005. View

Ashton T, McKenna W, Kunz-Schughart L, Higgins G . Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. Clin Cancer Res. 2018; 24(11):2482-2490. DOI: 10.1158/1078-0432.CCR-17-3070. View

Bader J, Voss K, Rathmell J . Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. Mol Cell. 2020; 78(6):1019-1033. PMC: 7339967. DOI: 10.1016/j.molcel.2020.05.034. View

Badgeley A, Anwar H, Modi K, Murphy P, Lakshmikuttyamma A . Effect of probiotics and gut microbiota on anti-cancer drugs: Mechanistic perspectives. Biochim Biophys Acta Rev Cancer. 2020; 1875(1):188494. DOI: 10.1016/j.bbcan.2020.188494. View

Bartolini D, Torquato P, Piroddi M, Galli F . Targeting glutathione S-transferase P and its interactome with selenium compounds in cancer therapy. Biochim Biophys Acta Gen Subj. 2018; 1863(1):130-143. DOI: 10.1016/j.bbagen.2018.09.023. View

Bhattacharya B, Omar M, Soong R . The Warburg effect and drug resistance. Br J Pharmacol. 2016; 173(6):970-9. PMC: 4793921. DOI: 10.1111/bph.13422. View

Bock F, Tait S . Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2019; 21(2):85-100. DOI: 10.1038/s41580-019-0173-8. View

Borrelli A, Bonelli P, Tuccillo F, Goldfine I, Evans J, Buonaguro F . Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biol. 2018; 15:467-479. PMC: 5975181. DOI: 10.1016/j.redox.2018.01.009. View

10.

Burke P . Mitochondria, Bioenergetics and Apoptosis in Cancer. Trends Cancer. 2017; 3(12):857-870. PMC: 5957506. DOI: 10.1016/j.trecan.2017.10.006. View

11.

Cao Y . Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest. 2019; 129(8):3006-3017. PMC: 6668696. DOI: 10.1172/JCI127201. View

12.

Chen X, Hao B, Li D, Reiter R, Bai Y, Abay B . Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis. J Pineal Res. 2021; 71(2):e12755. DOI: 10.1111/jpi.12755. View

13.

Chi H, Chen S, Lin S, Tsai C, Chuang W, Lin Y . Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover. Oncogene. 2017; 36(37):5274-5284. DOI: 10.1038/onc.2017.136. View

14.

Cao Z, Sun B, Zhao X, Zhang Y, Gu Q, Liang X . Correction: Cao, Z., et al. The Expression and Functional Significance of Runx2 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry and Epithelial-Mesenchymal Transition. 2017, , 500. Int J Mol Sci. 2020; 22(1). PMC: 7795879. DOI: 10.3390/ijms22010077. View

15.

Ferro F, Servais S, Besson P, Roger S, Dumas J, Brisson L . Autophagy and mitophagy in cancer metabolic remodelling. Semin Cell Dev Biol. 2019; 98:129-138. DOI: 10.1016/j.semcdb.2019.05.029. View

16.

Genovese I, Vezzani B, Danese A, Modesti L, Vitto V, Corazzi V . Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies. Cell Calcium. 2020; 92:102308. DOI: 10.1016/j.ceca.2020.102308. View

17.

Gentric G, Kieffer Y, Mieulet V, Goundiam O, Bonneau C, Nemati F . PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metab. 2018; 29(1):156-173.e10. PMC: 6331342. DOI: 10.1016/j.cmet.2018.09.002. View

18.

Gottesman M . Mechanisms of cancer drug resistance. Annu Rev Med. 2002; 53:615-27. DOI: 10.1146/annurev.med.53.082901.103929. View

19.

Halbrook C, Lyssiotis C . Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. Cancer Cell. 2017; 31(1):5-19. DOI: 10.1016/j.ccell.2016.12.006. View

20.

Hargreaves I . Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol. 2014; 49:105-11. DOI: 10.1016/j.biocel.2014.01.020. View