The Red Pepper's Spicy Ingredient Capsaicin Activates AMPK in HepG2 Cells Through CaMKKβ

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Jan 30

PMID 30695053

Citations 14

Authors

Alicia Bort

Belen G Sanchez

Elena Spinola

Pedro A Mateos-Gomez

Nieves Rodriguez-Henche

Ines Diaz-Laviada

Affiliations

Soon will be listed here.

Abstract

Capsaicin is a natural compound present in chili and red peppers and the responsible of their spicy flavor. It has recently provoked interest because of its antitumoral effects in many cell types although its action mechanism is not clearly understood. As metabolic dysregulation is one of the hallmarks of cancer cells and the key metabolic sensor in the AMP-activated kinase (AMPK), in this study we explored the ability of capsaicin to modulate AMPK activity. We found that capsaicin activated AMPK in HepG2 cells by increasing AMPK phosphorylation and its downstream target ACC. Mechanistically, we determined that capsaicin activated AMPK through the calcium/calmodulin-dependent protein kinase kinase β, CaMKKβ as either the CaMKK inhibitor STO-609 or CaMKK knock down with siRNA abrogated the activation of AMPK. Moreover, capsaicin decreased cell viability, inhibited Akt/mTOR pathway and increased reactive oxygen species (ROS) in HepG2 cells. AMPK activation was involved in the underpinning mechanism of capsaicin-induced cell death.

Citing Articles

Two Triterpenoids, ARM-2 and RA-5, From Exhibit the Potential to Modulate Lipolysis and Lipogenesis in Cultured 3T3-L1 Adipocytes.

Ndlovu M, Serem J, Bester M, Apostolides Z, Opoku A, Mosa R J Lipids. 2024; 2024:3972941.

PMID: 39450349 PMC: 11502128. DOI: 10.1155/2024/3972941.

Capsaicin: a spicy way in liver disease.

Li S, Hao L, Yu F, Li N, Deng J, Zhang J Front Pharmacol. 2024; 15:1451084.

PMID: 39281271 PMC: 11392895. DOI: 10.3389/fphar.2024.1451084.

Will AMPK be a potential therapeutic target for hepatocellular carcinoma?.

Chen G, Li M, Yang J, Zhou Z Am J Cancer Res. 2024; 14(7):3241-3258.

PMID: 39113872 PMC: 11301289. DOI: 10.62347/YAVK1315.

Capsaicin Alters the Expression of Genetic and Epigenetic Molecules In Hepatocellular Carcinoma Cell.

Ates B, Oner C, Akbulut Z, Colak E Int J Mol Cell Med. 2023; 11(3):236-243.

PMID: 37605741 PMC: 10440001. DOI: 10.22088/IJMCM.BUMS.11.3.236.

Capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of hepatic progenitor cells via SIRT1/SOX2 signaling pathway.

Xie Z, Li H, Hou X, Huang M, Zhu Z, Wei L Cancer Med. 2022; 11(22):4283-4296.

PMID: 35674129 PMC: 9678096. DOI: 10.1002/cam4.4777.

References

Li Z, Guan M, Lin Y, Cui X, Zhang Y, Zhao Z . Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Liver Lipidomics. Int J Mol Sci. 2017; 18(12). PMC: 5751153. DOI: 10.3390/ijms18122550. View

Friedman J, Nolan N, Brown K, Miles S, Akers A, Colclough K . Anticancer Activity of Natural and Synthetic Capsaicin Analogs. J Pharmacol Exp Ther. 2017; 364(3):462-473. PMC: 5803642. DOI: 10.1124/jpet.117.243691. View

Song J, Ren H, Gao Y, Lee C, Li S, Zhang F . Dietary Capsaicin Improves Glucose Homeostasis and Alters the Gut Microbiota in Obese Diabetic ob/ob Mice. Front Physiol. 2017; 8:602. PMC: 5575157. DOI: 10.3389/fphys.2017.00602. View

Ramos-Torres A, Bort A, Morell C, Rodriguez-Henche N, Diaz-Laviada I . The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget. 2015; 7(2):1569-83. PMC: 4811481. DOI: 10.18632/oncotarget.6415. View

Peng M, Darko K, Tao T, Huang Y, Su Q, He C . Combination of metformin with chemotherapeutic drugs via different molecular mechanisms. Cancer Treat Rev. 2017; 54:24-33. DOI: 10.1016/j.ctrv.2017.01.005. View

Chen X, Tan M, Xie Z, Feng B, Zhao Z, Yang K . Inhibiting ROS-STAT3-dependent autophagy enhanced capsaicin-induced apoptosis in human hepatocellular carcinoma cells. Free Radic Res. 2016; 50(7):744-55. DOI: 10.3109/10715762.2016.1173689. View

Diaz-Laviada I, Rodriguez-Henche N . The potential antitumor effects of capsaicin. Prog Drug Res. 2014; 68:181-208. DOI: 10.1007/978-3-0348-0828-6_8. View

Clark R, Lee S . Anticancer Properties of Capsaicin Against Human Cancer. Anticancer Res. 2016; 36(3):837-43. View

Narang N, Jiraungkoorskul W, Jamrus P . Current Understanding of Antiobesity Property of Capsaicin. Pharmacogn Rev. 2017; 11(21):23-26. PMC: 5414451. DOI: 10.4103/phrev.phrev_48_16. View

10.

Laker R, Drake J, Wilson R, Lira V, Lewellen B, Ryall K . Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun. 2017; 8(1):548. PMC: 5601463. DOI: 10.1038/s41467-017-00520-9. View

11.

Hawley S, Pan D, Mustard K, Ross L, Bain J, Edelman A . Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005; 2(1):9-19. DOI: 10.1016/j.cmet.2005.05.009. View

12.

Amantini C, Morelli M, Nabissi M, Cardinali C, Santoni M, Gismondi A . Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner. Oncotarget. 2016; 7(31):50180-50194. PMC: 5226576. DOI: 10.18632/oncotarget.10326. View

13.

Dulloo A . The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients. Obes Rev. 2011; 12(10):866-83. DOI: 10.1111/j.1467-789X.2011.00909.x. View

14.

Marcelo K, Means A, York B . The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft. Trends Endocrinol Metab. 2016; 27(10):706-718. PMC: 5035586. DOI: 10.1016/j.tem.2016.06.001. View

15.

Kang J, Goto T, Han I, Kawada T, Kim Y, Yu R . Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity (Silver Spring). 2009; 18(4):780-7. DOI: 10.1038/oby.2009.301. View

16.

Sun L, Suo C, Li S, Zhang H, Gao P . Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect. Biochim Biophys Acta Rev Cancer. 2018; 1870(1):51-66. DOI: 10.1016/j.bbcan.2018.06.005. View

17.

Fogarty S, Hawley S, Green K, Saner N, Mustard K, Grahame Hardie D . Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem J. 2009; 426(1):109-18. PMC: 2830670. DOI: 10.1042/BJ20091372. View

18.

Wang Y, Deng X, Yu C, Zhao G, Zhou J, Zhang G . Synergistic inhibitory effects of capsaicin combined with cisplatin on human osteosarcoma in culture and in xenografts. J Exp Clin Cancer Res. 2018; 37(1):251. PMC: 6192127. DOI: 10.1186/s13046-018-0922-0. View

19.

Ward P, Thompson C . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012; 21(3):297-308. PMC: 3311998. DOI: 10.1016/j.ccr.2012.02.014. View

20.

Shen W, Shen M, Zhao X, Zhu H, Yang Y, Lu S . Anti-obesity Effect of Capsaicin in Mice Fed with High-Fat Diet Is Associated with an Increase in Population of the Gut Bacterium . Front Microbiol. 2017; 8:272. PMC: 5322252. DOI: 10.3389/fmicb.2017.00272. View