Protein Kinase C Inhibitor Chelerythrine Selectively Inhibits Proliferation of Triple-negative Breast Cancer Cells

Overview

Journal Sci Rep

Specialty Science

Date 2017 May 19

PMID 28515445

Citations 30

Authors

Wanjun Lin

Jiajun Huang

Zhongwen Yuan

Senling Feng

Ying Xie

Wenzhe Ma

Affiliations

Soon will be listed here.

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targeted therapy currently. Recent studies imply that protein kinase C may play important roles in TNBC development and could be a specific target. In this study, we evaluated the anti-proliferative activity of PKC inhibitor chelerythrine on a panel of breast cancer cell lines. Chelerythrine selectively inhibited the growth of TNBC cell lines compared to non-TNBC cell lines as demonstrated by in vitro cell proliferation assay and colony formation assay, as well as evidenced by in vivo xenograft assay. The selective anti-proliferative effect of chelerythrine was associated with induction of apoptosis in TNBC cell lines. We further demonstrated that PKN2, one of the PKC subtypes, was highly expressed in TNBC cell lines, and knocking down PKN2 in TNBC cells inhibited colony formation and xenograft growth. This indicates that PKN2 is required for the survival of TNBC cells, and could be the target mediates the selective activity of chelerythrine. Finally, combination of chelerythrine and chemotherapy reagent taxol showed synergistic/additive effect on TNBC cell lines. Our results suggest chelerythrine or other PKC inhibitors may be promising regimens for TNBC tumors.

Citing Articles

Tanshinlactone triggers methuosis in breast cancer cells via NRF2 activation.

Lin W, Huang Z, Zhang X, Zheng D, Yang Y, Shi M Front Pharmacol. 2025; 15:1534217.

PMID: 39906392 PMC: 11790599. DOI: 10.3389/fphar.2024.1534217.

Chelerythrine triggers the prolongation of QT interval and induces cardiotoxicity by promoting the degradation of hERG channels.

Wang F, Wang B, Gu X, Li X, Liu X, Li B J Biol Chem. 2024; 301(1):108023.

PMID: 39608718 PMC: 11721429. DOI: 10.1016/j.jbc.2024.108023.

PKC inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability.

Yu J, Xiang Y, Gao Y, Chang S, Kong R, Lv X Acta Pharm Sin B. 2024; 14(10):4378-4395.

PMID: 39525583 PMC: 11544271. DOI: 10.1016/j.apsb.2024.08.003.

Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages.

Iglesia M, Jayasinghe R, Chen S, Terekhanova N, Herndon J, Storrs E Nat Cancer. 2024; 5(11):1713-1736.

PMID: 39478117 PMC: 11584403. DOI: 10.1038/s43018-024-00773-6.

De novo production of protoberberine and benzophenanthridine alkaloids through metabolic engineering of yeast.

Jiao X, Fu X, Li Q, Bu J, Liu X, Savolainen O Nat Commun. 2024; 15(1):8759.

PMID: 39384562 PMC: 11464499. DOI: 10.1038/s41467-024-53045-3.

References

Tam W, Lu H, Buikhuisen J, Soh B, Lim E, Reinhardt F . Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell. 2013; 24(3):347-64. PMC: 4001722. DOI: 10.1016/j.ccr.2013.08.005. View

Calautti E, Grossi M, Mammucari C, Aoyama Y, Pirro M, Ono Y . Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol. 2002; 156(1):137-48. PMC: 2173591. DOI: 10.1083/jcb.200105140. View

Murphy S, Frishman W . Protein kinase C in cardiac disease and as a potential therapeutic target. Cardiol Rev. 2004; 13(1):3-12. DOI: 10.1097/01.crd.0000124914.59755.8d. View

Hauner D, Hauner H . Metabolic syndrome and breast cancer: is there a link?. Breast Care (Basel). 2014; 9(4):277-81. PMC: 4209278. DOI: 10.1159/000365951. View

Bradshaw P, Stevens J, Khankari N, Teitelbaum S, Neugut A, Gammon M . Cardiovascular Disease Mortality Among Breast Cancer Survivors. Epidemiology. 2015; 27(1):6-13. PMC: 4666721. DOI: 10.1097/EDE.0000000000000394. View

Foulkes W, Smith I, Reis-Filho J . Triple-negative breast cancer. N Engl J Med. 2010; 363(20):1938-48. DOI: 10.1056/NEJMra1001389. View

Koh H, Lee K, Kim D, Kim S, Kim J, Chung J . Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000; 275(44):34451-8. DOI: 10.1074/jbc.M001753200. View

Zhang Z, Guo Y, Zhang J, Wei X . Induction of apoptosis by chelerythrine chloride through mitochondrial pathway and Bcl-2 family proteins in human hepatoma SMMC-7721 cell. Arch Pharm Res. 2011; 34(5):791-800. DOI: 10.1007/s12272-011-0513-5. View

Fabbro D, Kung W, ROOS W, Regazzi R, Eppenberger U . Epidermal growth factor binding and protein kinase C activities in human breast cancer cell lines: possible quantitative relationship. Cancer Res. 1986; 46(6):2720-5. View

10.

Garg R, Benedetti L, Abera M, Wang H, Abba M, Kazanietz M . Protein kinase C and cancer: what we know and what we do not. Oncogene. 2013; 33(45):5225-37. PMC: 4435965. DOI: 10.1038/onc.2013.524. View

11.

Gross C, Heumann R, Erdmann K . The protein kinase C-related kinase PRK2 interacts with the protein tyrosine phosphatase PTP-BL via a novel PDZ domain binding motif. FEBS Lett. 2001; 496(2-3):101-4. DOI: 10.1016/s0014-5793(01)02401-2. View

12.

Tonetti D, Chisamore M, Grdina W, Schurz H, Jordan V . Stable transfection of protein kinase C alpha cDNA in hormone-dependent breast cancer cell lines. Br J Cancer. 2000; 83(6):782-91. PMC: 2363523. DOI: 10.1054/bjoc.2000.1326. View

13.

Churchill E, Budas G, Vallentin A, Koyanagi T, Mochly-Rosen D . PKC isozymes in chronic cardiac disease: possible therapeutic targets?. Annu Rev Pharmacol Toxicol. 2007; 48:569-99. DOI: 10.1146/annurev.pharmtox.48.121806.154902. View

14.

Chen X, Zhang M, Fan P, Qin Y, Zhao H . Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines. Oncol Lett. 2016; 11(6):3917-3924. PMC: 4888265. DOI: 10.3892/ol.2016.4520. View

15.

Shen L, Dean N, Glazer R . Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide. Mol Pharmacol. 1999; 55(2):396-402. DOI: 10.1124/mol.55.2.396. View

16.

Kumar S, Tomar M, Acharya A . Activation of p53-dependent/-independent pathways of apoptotic cell death by chelerythrine in a murine T cell lymphoma. Leuk Lymphoma. 2014; 56(6):1846-55. DOI: 10.3109/10428194.2014.974042. View

17.

Deepak P, Kumar S, Gautam P, Acharya A . A benzophenanthridine alkaloid, chelerythrine induces apoptosis in vitro in a Dalton's lymphoma. J Cancer Res Ther. 2014; 9(4):693-700. DOI: 10.4103/0973-1482.126485. View

18.

Crown J, OShaughnessy J, Gullo G . Emerging targeted therapies in triple-negative breast cancer. Ann Oncol. 2012; 23 Suppl 6:vi56-65. DOI: 10.1093/annonc/mds196. View

19.

Funakoshi T, Aki T, Nakayama H, Watanuki Y, Imori S, Uemura K . Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine. Toxicol In Vitro. 2011; 25(8):1581-7. DOI: 10.1016/j.tiv.2011.05.028. View

20.

Obrian C, Vogel V, Singletary S, Ward N . Elevated protein kinase C expression in human breast tumor biopsies relative to normal breast tissue. Cancer Res. 1989; 49(12):3215-7. View