Exploring the Anticancer Mechanism of Cardiac Glycosides Using Proteome Integral Solubility Alteration Approach

Overview

Journal Cancer Med

Specialty Oncology

Date 2024 Oct 1

PMID 39350574

Authors

Wenjie Qin

Yinhua Deng

Huan Ren

Yanling Liu

Ling Liu

Wenhui Liu

Yuxi Zhao

Chen Li

Zhiling Yang

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti-cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function.

Methods: We conducted lysate-based and intact-cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein-CG interactions. Public data including gene expression changes upon CG treatment were re-analyzed for validation.

Results: The PISA assays revealed CGs' broad-spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re-analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways.

Conclusion: Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential.

Citing Articles

Correction to "Exploring the Anticancer Mechanism of Cardiac Glycosides Using Proteome Integral Solubility Alteration Approach".

Cancer Med. 2024; 13(21):e70381.

PMID: 39506282 PMC: 11540830. DOI: 10.1002/cam4.70381.

Exploring the anticancer mechanism of cardiac glycosides using proteome integral solubility alteration approach.

Qin W, Deng Y, Ren H, Liu Y, Liu L, Liu W Cancer Med. 2024; 13(18):e70252.

PMID: 39350574 PMC: 11442762. DOI: 10.1002/cam4.70252.

References

Tan C, Go K, Bisteau X, Dai L, Yong C, Prabhu N . Thermal proximity coaggregation for system-wide profiling of protein complex dynamics in cells. Science. 2018; 359(6380):1170-1177. DOI: 10.1126/science.aan0346. View

Chong C, Sullivan Jr D . New uses for old drugs. Nature. 2007; 448(7154):645-6. DOI: 10.1038/448645a. View

Ma J, Chen T, Wu S, Yang C, Bai M, Shu K . iProX: an integrated proteome resource. Nucleic Acids Res. 2018; 47(D1):D1211-D1217. PMC: 6323926. DOI: 10.1093/nar/gky869. View

Changeux J, Christopoulos A . Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell. 2016; 166(5):1084-1102. DOI: 10.1016/j.cell.2016.08.015. View

Zhang Z, Qiao Y, Sun Q, Peng L, Sun L . A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability. Cell Death Discov. 2023; 9(1):350. PMC: 10518014. DOI: 10.1038/s41420-023-01640-6. View

Huang R, Xia M, Sakamuru S, Zhao J, Shahane S, Attene-Ramos M . Modelling the Tox21 10 K chemical profiles for in vivo toxicity prediction and mechanism characterization. Nat Commun. 2016; 7:10425. PMC: 4777217. DOI: 10.1038/ncomms10425. View

Jung F, Frey K, Zimmer D, Muhlhaus T . DeepSTABp: A Deep Learning Approach for the Prediction of Thermal Protein Stability. Int J Mol Sci. 2023; 24(8). PMC: 10138888. DOI: 10.3390/ijms24087444. View

Gerke V, Gavins F, Geisow M, Grewal T, Jaiswal J, Nylandsted J . Annexins-a family of proteins with distinctive tastes for cell signaling and membrane dynamics. Nat Commun. 2024; 15(1):1574. PMC: 10882027. DOI: 10.1038/s41467-024-45954-0. View

Ashburn T, Thor K . Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004; 3(8):673-83. DOI: 10.1038/nrd1468. View

10.

Franken H, Mathieson T, Childs D, Sweetman G, Werner T, Togel I . Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry. Nat Protoc. 2015; 10(10):1567-93. DOI: 10.1038/nprot.2015.101. View

11.

Yang S, Hwang S, Kim M, Seo S, Lee J, Jeong S . Mitochondrial glutamine metabolism via GOT2 supports pancreatic cancer growth through senescence inhibition. Cell Death Dis. 2018; 9(2):55. PMC: 5833441. DOI: 10.1038/s41419-017-0089-1. View

12.

Qi J, Li M, Wang L, Hu Y, Liu W, Long Z . National and subnational trends in cancer burden in China, 2005-20: an analysis of national mortality surveillance data. Lancet Public Health. 2023; 8(12):e943-e955. DOI: 10.1016/S2468-2667(23)00211-6. View

13.

Dieckhaus H, Brocidiacono M, Randolph N, Kuhlman B . Transfer learning to leverage larger datasets for improved prediction of protein stability changes. Proc Natl Acad Sci U S A. 2024; 121(6):e2314853121. PMC: 10861915. DOI: 10.1073/pnas.2314853121. View

14.

Ouyang X, Han S, Zhang J, Dioletis E, Nemeth B, Pacher P . Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metab. 2018; 27(2):339-350.e3. PMC: 5806149. DOI: 10.1016/j.cmet.2018.01.007. View

15.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

16.

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

17.

Fernandez H, Gadre S, Tan M, Graham G, Mosaoa R, Ongkeko M . The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer. Cell Death Differ. 2018; 25(7):1239-1258. PMC: 6030199. DOI: 10.1038/s41418-018-0101-z. View

18.

Shen J, Zhan Y, Li H, Wang Z . Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines. Acta Pharmacol Sin. 2019; 41(1):110-118. PMC: 7468359. DOI: 10.1038/s41401-019-0290-0. View

19.

Hou C, Wang X, Xie H, Chen T, Zhu P, Xu X . PhaSepDB in 2022: annotating phase separation-related proteins with droplet states, co-phase separation partners and other experimental information. Nucleic Acids Res. 2022; 51(D1):D460-D465. PMC: 9825587. DOI: 10.1093/nar/gkac783. View

20.

Wang Y, Patti G . The Warburg effect: a signature of mitochondrial overload. Trends Cell Biol. 2023; 33(12):1014-1020. PMC: 10600323. DOI: 10.1016/j.tcb.2023.03.013. View