The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes

  • Authors:
    • Mengjing Zhao
    • Cai Wei
    • Xue Yang
    • Juan Zhou
    • Jing Wang
    • Fang Gu
    • Ting Lei
    • Yide Qin
  • View Affiliations

  • Published online on: February 12, 2016     https://doi.org/10.3892/ijo.2016.3390
  • Pages: 1721-1729
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Some bioactive peptides derived from natural resources or synthesized by rational design have been proved to have very good anticancer effect. We studied the inhibition of PGPIPN, a hexapeptide derived from bovine β-casein, on the invasion and metastasis of human ovarian cancer cells in vitro and its molecular mechanism. The human ovarian cancer cells studied include the cell line SKOV3 as well as the primary ovarian cancer cells from ovarian tumor tissues of 37 patients at initial debulking surgery, diagnosed as serous ovarian adenocarcinoma. We showed that PGPIPN inhibited the invasion of ovarian cancer cells with Transwell chamber assay, the migration of ovarian cancer cells with cell scratch assay and colony formation of ovarian cancer cells. The expression (mRNAs and proteins) of genes relevant to invasion and metastasis, MTA1, and NM23H1 were analyzed by real-time PCR and western blotting. PGPIPN repressed the expression of MTA1, and promoted NM23H1. The effects of PGPIPN were dose-dependent. Thus, our study suggests that PGPIPN is a potential therapeutic agent for adjuvant therapy of human malignant ovarian tumors.

References

1 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Hennessy BT, Coleman RL and Markman M: Ovarian cancer. Lancet. 374:1371–1382. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RH, van der Burg ME, Lacave AJ, Panici PB, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 363:943–953. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Jayson GC, Kohn EC, Kitchener HC and Ledermann JA: Ovarian cancer. Lancet. 384:1376–1388. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Baldi A, Ioannis P, Chiara P, Eleonora F, Roubini C and Vittorio D: Biological effects of milk proteins and their peptides with emphasis on those related to the gastrointestinal ecosystem. J Dairy Res. 72(S1): 66–72. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Walhout AJ, Sordella R, Lu X, Hartley JL, Temple GF, Brasch MA, Thierry-Mieg N and Vidal M: Protein interaction mapping in C. elegans using proteins involved in vulval development. Science. 287:116–122. 2000. View Article : Google Scholar

7 

Zhou J, Chen J, Mokotoff M and Ball ED: Targeting gastrin-releasing peptide receptors for cancer treatment. Anticancer Drugs. 15:921–927. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Mader JS and Hoskin DW: Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs. 15:933–946. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Wang W, Gu F, Wei C, Tang Y, Zheng X, Ren M and Qin Y: PGPIPN, a therapeutic hexapeptide, suppressed human ovarian cancer growth by targeting BCL2. PLoS One. 8:e607012013. View Article : Google Scholar : PubMed/NCBI

10 

Fiat AM, Migliore-Samour D, Jollès P, Drouet L, Bal dit Sollier C and Caen J: Biologically active peptides from milk proteins with emphasis on two examples concerning antithrombotic and immunomodulating activities. J Dairy Sci. 76:301–310. 1993. View Article : Google Scholar : PubMed/NCBI

11 

Ganjam LS, Thornton WH Jr, Marshall RT and MacDonald RS: Antiproliferative effects of yogurt fractions obtained by membrane dialysis on cultured mammalian intestinal cells. J Dairy Sci. 80:2325–2329. 1997. View Article : Google Scholar : PubMed/NCBI

12 

Kayser H and Meisel H: Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins. FEBS Lett. 383:18–20. 1996. View Article : Google Scholar : PubMed/NCBI

13 

Meisel H: Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers. 43:119–128. 1997. View Article : Google Scholar : PubMed/NCBI

14 

Meisel H and FitzGerald RJ: Biofunctional peptides from milk proteins: Mineral binding and cytomodulatory effects. Curr Pharm Des. 9:1289–1295. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

16 

Green MR and Sambrook J: Molecular Cloning: A Laboratory Manual. 4th edition. Cold Spring Habor Laboratory Press; New York, NY: 2012

17 

Chi JY, Hsiao YW, Li CF, Lo YC, Lin ZY, Hong JY, Liu YM, Han X, Wang SM, Chen BK, et al: Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers. Oncotarget. 6:23987–24001. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Shan D, Li J, Cai P, Prasad P, Liu F, Rauth AM and Wu XY: RGD-conjugated solid lipid nanoparticles inhibit adhesion and invasion of αvβ3 integrin-overexpressing breast cancer cells. Drug Deliv Transl Res. 5:15–26. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Chen HY, Mollstedt O, Tsai MH and Kreider RB: Potential clinical applications of multi-functional milk proteins and peptides in cancer management. Curr Med Chem. 21:2424–2437. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Nongonierma AB and FitzGerald RJ: Bioactive properties of milk proteins in humans: A review. Peptides. 73:20–34. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Bonuccelli G, Castello-Cros R, Capozza F, Martinez-Outschoorn UE, Lin Z, Tsirigos A, Xuanmao J, Whitaker-Menezes D, Howell A, Lisanti MP, et al: The milk protein α-casein functions as a tumor suppressor via activation of STAT1 signaling, effectively preventing breast cancer tumor growth and metastasis. Cell Cycle. 11:3972–3982. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Terasaki-Fukuzawa Y, Kijima H, Suto A, Takeshita T, Iezumi K, Sato S, Yoshida H, Sato T, Shimbori M and Shiina Y: Decreased nm23 expression, but not Ki-67 labeling index, is significantly correlated with lymph node metastasis of breast invasive ductal carcinoma. Int J Mol Med. 9:25–29. 2002.

23 

Pencil SD, Toh Y and Nicolson GL: Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat. 25:165–174. 1993. View Article : Google Scholar : PubMed/NCBI

24 

Toh Y, Pencil SD and Nicolson GL: A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem. 269:22958–22963. 1994.PubMed/NCBI

25 

Toh Y, Pencil SD and Nicolson GL: Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene. 159:97–104. 1995. View Article : Google Scholar : PubMed/NCBI

26 

Toh Y, Oki E, Oda S, Tokunaga E, Ohno S, Maehara Y, Nicolson GL and Sugimachi K: Overexpression of the MTA1 gene in gastrointestinal carcinomas: Correlation with invasion and metastasis. Int J Cancer. 74:459–463. 1997. View Article : Google Scholar : PubMed/NCBI

27 

Futamura M, Nishimori H, Shiratsuchi T, Saji S, Nakamura Y and Tokino T: Molecular cloning, mapping, and characterization of a novel human gene, MTA1-L1, showing homology to a metastasis-associated gene, MTA1. J Hum Genet. 44:52–56. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Liu H, Mao H and Fu X: Expression of nm23 in breast cancer: Correlation with distant metastasis and prognosis. Zhonghua Zhong Liu Za Zhi. 23:224–227. 2001.(In Chinese).

29 

Huang G, Song Y and He G: mRNA expression and mutation of MTA1 and nm23H1 genes in ovarian carcinoma in relation to lymph node metastasis. Zhonghua Zhong Liu Za Zhi. 23:31–34. 2001.(In Chinese).

30 

Kreider RB, Iosia M, Cooke M, Hudson G, Rasmussen C, Chen H, Mollstedt O and Tsai MH: Bioactive properties and clinical safety of a novel milk protein peptide. Nutr J. 10:992011. View Article : Google Scholar : PubMed/NCBI

31 

Fiedorowicz E, Jarmołowska B, Iwan M, Kostyra E, Obuchowicz R and Obuchowicz M: The influence of μ-opioid receptor agonist and antagonist peptides on peripheral blood mononuclear cells (PBMCs). Peptides. 32:707–712. 2011. View Article : Google Scholar

Related Articles

Journal Cover

April 2016
Volume 48 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhao, M., Wei, C., Yang, X., Zhou, J., Wang, J., Gu, F. ... Qin, Y. (2016). The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes. International Journal of Oncology, 48, 1721-1729. https://doi.org/10.3892/ijo.2016.3390
MLA
Zhao, M., Wei, C., Yang, X., Zhou, J., Wang, J., Gu, F., Lei, T., Qin, Y."The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes". International Journal of Oncology 48.4 (2016): 1721-1729.
Chicago
Zhao, M., Wei, C., Yang, X., Zhou, J., Wang, J., Gu, F., Lei, T., Qin, Y."The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes". International Journal of Oncology 48, no. 4 (2016): 1721-1729. https://doi.org/10.3892/ijo.2016.3390