Development of human prostate cancer stem cells involves epigenomic alteration and PI3K/AKT pathway activation
Tóm tắt
Human prostate cancer spheres endowed with stem cell properties have been obtained from androgen-dependent cell line LNCaP after exposure to an epigenomic modulator phenethyl isothiocynate (PEITC). Sphere cells can self-renew and grow with androgen, and also without androgen. Little is known about the signaling pathway and mechanism in the development of the stem cells in the spheres.
Expression of phosphoinositol-3 kinase (PI3K) pathway members and histone acetylation were quantified in the tumor spheres and LNCaP cells by western immunoblotting.
The level of phosphorylated AKT was significantly increased in the sphere stem cells than the LNCaP cells at an average of 7.4 folds (range 5.8–10.7 folds), whereas the P27 level was elevated 5.4 folds (range 4.8–6.3 folds) (
PEITC appears to regulate the epigenome through histone acetylation and activate the PI3K/AKT pathway in the LNCaP cells. This mechanism may be responsible in part for the development of the prostate cancer stem cells.
Từ khóa
Tài liệu tham khảo
Lin L, Yan L, Liu Y, Yuan F, Li H, Ni J. Incidence and death in 29 cancer groups in 2017 and trend analysis from 1990 to 2017 from the Global Burden of Disease Study. J Hematol Oncol. 2019;12(1):96.
Brikun I, Nusskern D, Freije D. An expanded biomarker panel for the detection of prostate cancer from urine DNA. Exp Hematol Oncol. 2019;8(1):13.
Zarrabi K, Paroya A, Wu S. Emerging therapeutic agents for genitourinary cancers. J Hematol Oncol. 2019;12(1):89.
Chen Y, Cang S, Han L, Liu C, Yang P, Solangi Z, Lu Q, Liu D, Chiao JW. Establishment of prostate cancer spheres from a prostate cancer cell line after phenethyl isothiocyanate treatment and discovery of androgen-dependent reversible differentiation between sphere and neuroendocrine cells. Oncotarget. 2016;7(18):26567–79.
Wang L, Liu D, Ahmed T, Chung FL, Conaway C, Chiao JW. Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. Int J Oncol. 2004;24(1):187–92.
Wang L, Wang WL, Zhang Y, Guo SP, Zhang J, Li QL. Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res. 2007;37(5):389–96.
Wang LG, Beklemisheva A, Liu XM, Ferrari AC, Feng J, Chiao JW. Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer. Mol Carcinog. 2007;46(1):24–31.
Wang LG, Chiao JW. Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review). Int J Oncol. 2010;37(3):533–9.
Chiao JW, Wu H, Ramaswamy G, Conaway CC, Chung FL, Wang L, Liu D. Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest. Carcinogenesis. 2004;25(8):1403–8.
Bartlett AH, Liang JW, Sandoval-Sierra JV, Fowke JH, Simonsick EM, Johnson KC, Mozhui K. Longitudinal study of leukocyte DNA methylation and biomarkers for cancer risk in older adults. Biomark Res. 2019;7(1):10.
Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13(22):2905–27.
Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019;12(1):71.
Katsuya H, Cook LBM, Rowan AG, Satou Y, Taylor GP, Bangham CRM. Phosphatidylinositol 3-kinase-δ (PI3K-δ) is a potential therapeutic target in adult T-cell leukemia-lymphoma. Biomark Res. 2018;6(1):24.
Datta K, Bellacosa A, Chan TO, Tsichlis PN. Akt is a direct target of the phosphatidylinositol 3-kinase. Activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells. J Biol Chem. 1996;271(48):30835–9.
Siddle K. Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol. 2011;47(1):R1–10.
Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009;458(7239):725–31.
Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature. 1985;315(6016):239–42.
Jiang W, He T, Liu S, Zheng Y, Xiang L, Pei X, Wang Z, Yang H. The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the β-catenin/SIRT3 signaling pathway in cervical cancer. J Hematol Oncol. 2018;11(1):139.
Telford WG, King LE, Fraker PJ. Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry. 1992;13(2):137–43.
Cang S, Feng J, Konno S, Han L, Liu K, Sharma SC, Choudhury M, Chiao JW. Deficient histone acetylation and excessive deacetylase activity as epigenomic marks of prostate cancer cells. Int J Oncol. 2009;35(6):1417–22.
Cang S, Ma Y, Chiao J-w, Liu D. Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells. Exp Hematol Oncol. 2014;3(1):5.
Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22(14):2954–63.
Peltier J, O’Neill A, Schaffer DV. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol. 2007;67(10):1348–61.
Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, Kreisberg JI. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res. 2002;8(4):1168–71.
Erdogan S, Turkekul K, Dibirdik I, Doganlar O, Doganlar ZB, Bilir A, Oktem G. Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway. Biomed Pharmacother. 2018;107:793–805.
Erdogan S, Doganlar O, Doganlar ZB, Serttas R, Turkekul K, Dibirdik I, Bilir A. The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-kappaB signaling. Life Sci. 2016;162:77–86.
Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 2009;106(1):268–73.
Marhold M, Tomasich E, El-Gazzar A, Heller G, Spittler A, Horvat R, Krainer M, Horak P. HIF1alpha regulates mTOR signaling and viability of prostate cancer stem cells. Mol Cancer Res. 2015;13(3):556–64.
Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell. 2000;103(2):263–71.
Cheung P, Tanner KG, Cheung WL, Sassone-Corsi P, Denu JM, Allis CD. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol Cell. 2000;5(6):905–15.
Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004;306(5694):279–83.
Delarue M, Montel F, Vignjevic D, Prost J, Joanny JF, Cappello G. Compressive stress inhibits proliferation in tumor spheroids through a volume limitation. Biophys J. 2014;107(8):1821–8.
LaRue KE, Khalil M, Freyer JP. Microenvironmental regulation of proliferation in multicellular spheroids is mediated through differential expression of cyclin-dependent kinase inhibitors. Cancer Res. 2004;64(5):1621–31.
Wartenberg M, Fischer K, Hescheler J, Sauer H. Modulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by cell cycle inhibitors. Biochim Biophys Acta. 2002;1589(1):49–62.
Xing H, Wang S, Hu K, Tao W, Li J, Gao Q, Yang X, Weng D, Lu Y, Ma D. Effect of the cyclin-dependent kinases inhibitor p27 on resistance of ovarian cancer multicellular spheroids to anticancer chemotherapy. J Cancer Res Clin Oncol. 2005;131(8):511–9.
Berton S, Belletti B, Wolf K, Canzonieri V, Lovat F, Vecchione A, Colombatti A, Friedl P, Baldassarre G. The tumor suppressor functions of p27(kip1) include control of the mesenchymal/amoeboid transition. Mol Cell Biol. 2009;29(18):5031–45.