Ursolic Acid Inhibits Breast Cancer Growth by Inhibiting Proliferation, Inducing Autophagy and Apoptosis, and Suppressing Inflammatory Responses Via the PI3K/AKT and NF-κB Signaling Pathways

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2017 Oct 19

PMID 29042957

Citations 41

Authors

Juan Luo

Yan-Ling Hu

Hong Wang

Affiliations

Soon will be listed here.

Abstract

Breast cancer, which is the second leading cause of cancer-associated mortality in women worldwide, develops from breast tissue. Chemotherapy is the most commonly used therapy to treat breast cancer. However, a number of natural plant-derived products have been suggested as alternative therapies to treat different types of cancer, such as breast cancer. The aim of the present study was to determine the anti-tumor effects of ursolic acid and its effect on apoptosis and inflammation in breast cancer cells. The anti-cancer effects of ursolic acid were evaluated using flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death. Cellular migration assays demonstrated that ursolic acid was able to suppress the invasive ability of breast cancer cells (P<0.05). In addition, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was downregulated following ursolic acid administration (P<0.05), leading to an upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05). Furthermore, the inflammatory response of breast cancer cells was assessed by measuring levels of nuclear factor (NF)-κB. Ursolic acid was found to downregulate NF-κB in breast cancer cells, thus inhibiting inflammation and preventing the progression of breast cancer (P<0.05). To the best of our knowledge, the present study is the first to assess the effect of ursolic acid on breast cancer cells through PI3K/AKT-regulated GSK and caspase-3 accompanied by NF-κB signaling pathways. The results of the present study regarding the potential underlying molecular mechanisms of ursolic acid may be used to develop novel therapeutic strategies for breast cancer treatment.

Citing Articles

Cancer-Specific Activation of the Vesicular Stomatitis Virus Matrix by Survivin Promoter in Breast Cancer Cells.

Valouzi A, Shahbazi M, Erfani-Moghadam V, Ramezani M, Shamsabadi F Mol Biotechnol. 2025; .

PMID: 39820852 DOI: 10.1007/s12033-024-01359-4.

Targeting autophagy for breast cancer prevention and therapy: From classical methods to phytochemical agents.

Rajabi S, Shakib H, Safari-Alighiarloo N, Maresca M, Hamzeloo-Moghadam M Iran J Basic Med Sci. 2024; 27(12):1475-1491.

PMID: 39539439 PMC: 11556757. DOI: 10.22038/ijbms.2024.79405.17201.

Improving Water Solubility and Skin Penetration of Ursolic Acid through a Nanofiber Process to Achieve Better In Vitro Anti-Breast Cancer Activity.

Fu H, Wu T, Ma C, Yen F Pharmaceutics. 2024; 16(9).

PMID: 39339184 PMC: 11434903. DOI: 10.3390/pharmaceutics16091147.

Are the Effects of Bioactive Components on Human Health a Myth?: Black Elderberry (Sambucus nigra L.) from Exotic Fruits.

Sanlier N, Ejder Z, Irmak E Curr Nutr Rep. 2024; 13(4):815-827.

PMID: 39278865 DOI: 10.1007/s13668-024-00572-6.

Potential Pharmacological Properties of Triterpene Derivatives of Ursolic Acid.

Khwaza V, Aderibigbe B Molecules. 2024; 29(16).

PMID: 39202963 PMC: 11356970. DOI: 10.3390/molecules29163884.

References

Kim D, Ko I, Kim B, Kim T, Kim S, Shin M . Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis. Physiol Behav. 2010; 101(5):660-5. DOI: 10.1016/j.physbeh.2010.09.021. View

Partridge A, Rumble R, Carey L, Come S, Davidson N, Di Leo A . Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014; 32(29):3307-29. PMC: 6076042. DOI: 10.1200/JCO.2014.56.7479. View

Achiwa Y, Hasegawa K, Komiya T, Udagawa Y . Ursolic acid induces Bax-dependent apoptosis through the caspase-3 pathway in endometrial cancer SNG-II cells. Oncol Rep. 2004; 13(1):51-7. View

Paasch U, Grunewald S, Fitzl G, Glander H . Deterioration of plasma membrane is associated with activated caspases in human spermatozoa. J Androl. 2003; 24(2):246-52. DOI: 10.1002/j.1939-4640.2003.tb02669.x. View

Zheng Q, Jin F, Yao C, Zhang T, Zhang G, Ai X . Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells. Biochem Biophys Res Commun. 2012; 419(4):741-7. DOI: 10.1016/j.bbrc.2012.02.093. View

Majewski I, Nuciforo P, Mittempergher L, Bosma A, Eidtmann H, Holmes E . PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. 2015; 33(12):1334-9. PMC: 5087318. DOI: 10.1200/JCO.2014.55.2158. View

Mouridsen H, Robert N . The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women. Eur J Cancer. 2005; 41(12):1678-89. DOI: 10.1016/j.ejca.2004.10.020. View

Shin D, Kim G, Lee J, Choi B, Yoo Y, Choi Y . Apoptosis induction of human prostate carcinoma DU145 cells by diallyl disulfide via modulation of JNK and PI3K/AKT signaling pathways. Int J Mol Sci. 2012; 13(11):14158-71. PMC: 3509573. DOI: 10.3390/ijms131114158. View

Marderosian M, Sharma A, Funk A, Vartanian R, Masri J, Jo O . Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene. 2006; 25(47):6277-90. DOI: 10.1038/sj.onc.1209645. View

10.

Li J, Liang X, Yang X . Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways. Oncol Rep. 2012; 28(2):501-10. DOI: 10.3892/or.2012.1827. View

11.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

12.

Fresno Vara J, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M . PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004; 30(2):193-204. DOI: 10.1016/j.ctrv.2003.07.007. View

13.

Liobikas J, Majiene D, Trumbeckaite S, Kursvietiene L, Masteikova R, Kopustinskiene D . Uncoupling and antioxidant effects of ursolic acid in isolated rat heart mitochondria. J Nat Prod. 2011; 74(7):1640-4. DOI: 10.1021/np200060p. View

14.

Zhang B, Ji X, Zhang S, Ren H, Wang M, Guo C . Hemin‑mediated neuroglobin induction exerts neuroprotection following ischemic brain injury through PI3K/Akt signaling. Mol Med Rep. 2013; 8(2):681-5. DOI: 10.3892/mmr.2013.1523. View

15.

Maeda S, Yoshida H, Ogura K, Mitsuno Y, Hirata Y, Yamaji Y . H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology. 2000; 119(1):97-108. DOI: 10.1053/gast.2000.8540. View

16.

Sanchez-Munoz A, Ribelles N, Alba E . Optimal adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer: have we answered the question?. Clin Transl Oncol. 2010; 12(9):614-20. DOI: 10.1007/s12094-010-0566-9. View

17.

Wang Y, Feng W, Xue W, Tan Y, Hein D, Li X . Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes. 2009; 58(6):1391-402. PMC: 2682666. DOI: 10.2337/db08-1697. View

18.

Prasad R, Vaid M, Katiyar S . Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway. PLoS One. 2012; 7(8):e43064. PMC: 3414463. DOI: 10.1371/journal.pone.0043064. View

19.

Floyd D, Zhang Y, Dey B, Kefas B, Breit H, Marks K . Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. PLoS One. 2014; 9(5):e96239. PMC: 4013090. DOI: 10.1371/journal.pone.0096239. View

20.

Bharti S, Golechha M, Kumari S, Siddiqui K, Arya D . Akt/GSK-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia-reperfusion injury in rats. Eur J Nutr. 2011; 51(6):719-27. DOI: 10.1007/s00394-011-0251-y. View