Luteolin reduces cancer‑induced skeletal and cardiac muscle atrophy in a Lewis lung cancer mouse model

Chen,Tiejun; Li,Bin; Xu,Ye; Meng,Shuying; Wang,Yuan; Jiang,Yan

doi:10.3892/or.2018.6453

Luteolin reduces cancer‑induced skeletal and cardiac muscle atrophy in a Lewis lung cancer mouse model

Authors:
- Tiejun Chen
- Bin Li
- Ye Xu
- Shuying Meng
- Yuan Wang
- Yan Jiang
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Affiliations: Department of Medical Oncology, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China, Department of Medical Oncology, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China, Geriatric Department, General Hospital of Benxi Iron and Steel Co., Ltd., Benxi, Liaoning 117000, P.R. China, Translational Medical Laboratory, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China, Translational Medical Laboratory, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China
Published online on: May 21, 2018 https://doi.org/10.3892/or.2018.6453
Pages: 1129-1137

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Abstract

Luteolin was recently demonstrated to suppress tumor growth by interfering with nuclear factor (NF)‑κB activation. As the NF‑κB pathway plays a critical role in muscular atrophy associated with cancer cachexia, we aimed to investigate the potential of luteolin to alleviate cancer‑associated cachexia in a Lewis lung cancer mouse model. C57BL/6 mice were divided into three groups: A control group, a model group and a luteolin group. Mice in the model and luteolin groups received a subcutaneous injection of Lewis lung cancer cells, while the control group received PBS. Subsequently, the tumor mass, serum, gastrocnemius muscle and heart were collected on day 21. The serum, gastrocnemius muscle and heart were weighed and prepared for use in enzyme‑linked immunosorbent assay (ELISA), western blotting (WB) and quantitative reverse transcription polymerase chain reaction (qRT‑PCR) analyses. The results revealed that the tumor‑free body mass was significantly reduced in tumor‑bearing mice compared with that of mice in the other groups. The gastrocnemius muscle mass and heart mass were greater in the luteolin treatment group than in the control group. Tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 levels were lower in the luteolin treatment group than in the model group. In addition, according to the results of the WB and qRT‑PCR analyses, the expression of the E3 ubiquitin ligase muscle RING finger‑containing protein 1 (MuRF1) was downregulated in skeletal muscle and cardiac muscle, whereas atrogin‑1 was downregulated only in skeletal muscle in the luteolin treatment group vs. the model group. Furthermore, IκB kinase β (IKKβ) and phospho‑p65 were significantly downregulated in skeletal muscle and cardiac tissue, whereas the expression of p‑p38 was downregulated only in skeletal muscle in the luteolin treatment group when compared with their expression levels in the model group, as determined by the WB analysis. In conclusion, from the current results, we conclude that luteolin is able to reduce inflammatory burden, downregulate the expression of genes associated with muscle protein breakdown, and protect skeletal and heart muscle from cancer‑induced wasting and loss in vivo. Therefore, luteolin has the potential to be developed into a novel anti‑cachetic agent.

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1	Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, et al: Definition and classifi cation of cancer cachexia: An international consensus. Lancet Oncol. 12:489–495. 2011. View Article : Google Scholar : PubMed/NCBI
2	Argilés JM, Busquets S, Stemmler B and López-Soriano FJ: Cancer cachexia: Understanding the molecular basis. Nat Rev Cancer. 14:754–762. 2014. View Article : Google Scholar : PubMed/NCBI
3	Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, et al: Cachexia: A new definition. Clin Nutr. 27:793–799. 2008. View Article : Google Scholar : PubMed/NCBI
4	Bilir C, Engin H, Can M, Temi YB and Demirtas D: The prognostic role of inflammation and hormones in patients with metastatic cancer with cachexia. Med Oncol. 32:562015. View Article : Google Scholar : PubMed/NCBI
5	Vaughan VC, Martin P and Lewandowski PA: Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle. 4:95–100. 2013. View Article : Google Scholar : PubMed/NCBI
6	Tisdale MJ: Mechanisms of cancer cachexia. Physiol Rev. 89:381–410. 2009. View Article : Google Scholar : PubMed/NCBI
7	Fearon KC, Glass DJ and Guttridge DC: Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell Metab. 16:153–166. 2012. View Article : Google Scholar : PubMed/NCBI
8	Schcolnik-Cabrera A, Chávez-Blanco A, Domínguez-Gómez G and Dueñas-González A: Understanding tumor anabolism and patient catabolism in cancer-associated cachexia. Am J Cancer Res. 7:1107–1135. 2017.PubMed/NCBI
9	Li H, Malhotra S and Kumar A: Nuclear factor-kappa B signaling in skeletal muscle atrophy. J Mol Med. 86:1113–1126. 2008. View Article : Google Scholar : PubMed/NCBI
10	Rhoads MG, Kandarian SC, Pacelli F, Doglietto GB and Bossola M: Expression of NF-kappaB and IkappaB proteins in skeletal muscle of gastric cancer patients. Eur J Cancer. 46:191–197. 2010. View Article : Google Scholar : PubMed/NCBI
11	Wysong A, Couch M, Shadfar S, Li L, Rodriguez JE, Asher S, Yin X, Gore M, Baldwin A, Patterson C, et al: NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. Am J Pathol. 178:1059–1068. 2011. View Article : Google Scholar : PubMed/NCBI
12	Tuorkey MJ: Molecular targets of luteolin in cancer. Eur J Cancer Prev. 25:65–76. 2016. View Article : Google Scholar : PubMed/NCBI
13	Weng Z, Patel AB, Vasiadi M, Therianou A and Theoharides TC: Luteolin inhibits human keratinocyte activation and decreases NF-κB induction that is increased in psoriatic skin. PLoS One. 9:e907392014. View Article : Google Scholar : PubMed/NCBI
14	Merriman RL, Shackelford KA, Tanzer LR, Campbell JB, Bemis KG and Matsumoto K: Drug treatments for metastasis of the Lewis lung carcinoma: lack of correlation between inhibition of lung metastasis and survival. Cancer Res. 49:4509–4516. 1989.PubMed/NCBI
15	Au ED, Desai AP, Koniaris LG and Zimmers TA: The MEK-inhibitor selumetinib attenuates tumor growth and reduces IL-6 expression but does not protect against muscle wasting in Lewis lung cancer cachexia. Front Physiol. 7:6822017. View Article : Google Scholar : PubMed/NCBI
16	Chen X, Wu Y, Yang T, Wei M, Wang Y, Deng X, Shen C, Li W, Zhang H, Xu W, et al: Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. J Cachexia Sarcopenia Muscle. 7:225–232. 2016. View Article : Google Scholar : PubMed/NCBI
17	Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K and Tisdale M: Characterization of a cancer cachectic factor. Nature. 379:739–742. 1996. View Article : Google Scholar : PubMed/NCBI
18	Albrecht JT and Canada TW: Cachexia and anorexia in malignancy. Hematol Oncol Clin North Am. 10:791–800. 1996. View Article : Google Scholar : PubMed/NCBI
19	Mueller TC, Bachmann J, Prokopchuk O, Friess H and Martignoni ME: Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia - can findings from animal models be translated to humans? BMC Cancer. 16:752016. View Article : Google Scholar : PubMed/NCBI
20	Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, et al: Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 294:1704–1708. 2001. View Article : Google Scholar : PubMed/NCBI
21	Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ and Shoelson SE: IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell. 119:285–298. 2004. View Article : Google Scholar : PubMed/NCBI
22	Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E and Glass DJ: The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab. 6:376–385. 2007. View Article : Google Scholar : PubMed/NCBI
23	Carson JA and Baltgalvis KA: Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev. 38:168–176. 2010. View Article : Google Scholar : PubMed/NCBI
24	Sun M, Ye Y, Xiao L, Duan X, Zhang Y and Zhang H: Anticancer effects of ginsenoside Rg3 (Review). Int J Mol Med. 39:507–518. 2017. View Article : Google Scholar : PubMed/NCBI
25	Li B, Wan L, Li Y, Yu Q, Chen P, Gan R, Yang Q, Han Y and Guo C: Baicalin, a component of Scutellaria baicalensis, alleviates anorexia and inhibits skeletal muscle atrophy in experimental cancer cachexia. Tumour Biol. 35:12415–12425. 2014. View Article : Google Scholar : PubMed/NCBI
26	Van Gammeren D, Damrauer JS, Jackman RW and Kandarian SC: The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy. FASEB J. 23:362–370. 2009. View Article : Google Scholar : PubMed/NCBI
27	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI
28	Willis MS, Rojas M, Li L, Selzman CH, Tang RH, Stansfield WE, Rodriguez JE, Glass DJ and Patterson C: Muscle ring finger 1 mediates cardiac atrophy in vivo. Am J Physiol Heart Circ Physiol. 296:H997–H1006. 2009. View Article : Google Scholar : PubMed/NCBI
29	Egerman MA and Glass DJ: Signaling pathways controlling skeletal muscle mass. Cric Rev Biochem Mol Biol. 49:59–68. 2014. View Article : Google Scholar
30	Waddell DS, Baehr LM, van den Brandt J, Johnsen SA, Reichardt HM, Furlow JD and Bodine SC: The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab. 295:E785–E797. 2008. View Article : Google Scholar : PubMed/NCBI
31	Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD and Glass DJ: The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 14:395–403. 2004. View Article : Google Scholar : PubMed/NCBI
32	Sacheck JM, Ohtsuka A, McLary SC and Goldberg AL: IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab. 287:E591–E601. 2004. View Article : Google Scholar : PubMed/NCBI