http://dx.doi.org/10.18081/2333-5106/017-161-175
Jones Lorenzoni; Lutz Hartsell; Johnstone Rades
Abstract
Localized prostate cancer (PCa) has a high cure rate, but chemotherapy resistance is common in the hormone-refractory setting. The biological factor(s) for chemotherapy resistance in localized PCa is(are) not well understood. Notch 3 signaling contributes to stem-cell maintenance in neural prostates. It is not activated in the normal prostate epithelial cells but is linked to the progression of metastatic PCa. We screened 1,064 proteins for their cellular abundance changes in 10-fold enriched ALDH1-expressing prostate cancer stem cells (PCSC) from hormone-independent PCa xenografts (PC3), LAPC-4 castration-resistant xenografts, hormone-dependent LAPC-4 xenografts, radiation-selected DU145, or hormone-dependent LNCaP progenitor cell xenografts by the RAQ method and identified 50 overexpressed stem-cell-refractory therapy proteins. Notch 3 is inappropriately signaling in PCa, and diseases associated with gain-of-function Notch mutations (especially in Notch 3 genes) are proliferative and apoptotically resistant. Notch 3 is intrinsically upregulated in cancer stem cells with glycolytic metabolism. Both the membrane and soluble forms of Notch 3 are proposed as potential therapeutic targets. We later discovered that Notch 3 has stronger loss-of-function mutations in 58 localized PCa. The top 13 most frequent somatic mutations in PCa do not fall in these genes and total to 77% of all known PCa mutations. They overwhelmingly favor a system error; rather than a formula error, the purpose of the Human Genome Project (HGP) is to identify glitches in 4,000 common DNA repair genes.
Keywords: Prostate cancer; Notch 3; multivariate analysis; chemotherapy
References
1. Stratton J, Godwin M. The effect of supplemental vitamins and minerals on the development of prostate cancer: A systematic review and meta-analysis. Family practice 2011;28 (3): 243–52.
2. Baade PD, Youlden DR, Krnjacki LJ. International epidemiology of prostate cancer: geographical distribution and secular trends. Molecular nutrition & food research 2009; 53 (2): 171–84.
3. Miele L, Osborne B. Arbiter of differentiation and death: Notch signaling meets apoptosis. J Cell, Physiol 1999;181:393–409. [PubMed]
4. Weinmaster G. The ins and outs of notch signaling. Mol Cell Neurosci 1997;9:91–102. [PubMed]
5. Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene 2008; 27:5124–5131. [PubMed]
6. Dotto GP. Notch tumor suppressor function. Oncogene 2008;27:5115–5123. [PubMed]
7. Cohen EH, Robinson J, Margolis P, Gaut M, Alperson A, Feagin M. Prostate brachytherapy: the impact of smoking on recurrence and overall survival of localized prostate cancer. American Journal of BioMedicine 2013;1(2):58-72. [Abstract/Full-Text]
8. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003;3:565–576. [PubMed]
9. Sawey ET, Johnson JA, Crawford HC. Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway. Proc Natl Acad Sci USA 2007;104:19327–19332. [PubMed]
10. Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ. Dynamics of notch expression during murine prostate development tumorigenesis. Cancer Res 2001;61:7291–7297. [PubMed]
11. Villaronga MA, Bevan CL, Belandia B. Notch signaling: a potential therapeutic target in prostate cancer. Curr Cancer Drug Targets 2008;8:566–580. [PubMed]
10. Leong KG, Gao WQ. The Notch pathway in prostate development and cancer. Differentiation. 2008;76:699–716. [PubMed]
12. Santagata S, Demichelis F, Riva A, Varambally S, Hofer MD, Kutok JL, Kim R, Tang J, Montie JE, et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res 2004;64:6854–6857. [PubMed]
13. Nantermet PV, Xu J, Yu Y, Hodor P, Holder D, Adamski S, Gentile MA, Kimmel DB, et al. Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland. J Biol Chem 2004;279:1310–1322. [PubMed]
14. Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A, Hsieh CC, Altieri DC. A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 2008;10:R97. [PubMed]
15. Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, Shimizu K, Honma R, Yanagisawa Y,et al. NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res 2008;68:1881–1888. [PubMed]
16. Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP. Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. Oncogene 2003;22:1988–1997. [PubMed]
17. Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science 2005;307:1904–1909. [PubMed]
18. Fre S, Pallavi SK, Huyghe M, Lae M, Janssen KP, Robine S, Rtavanis-Tsakonas S, Louvard D. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 2009;106:6309–6314. [PubMed]
19. Ghaleb AM, Aggarwal G, Bialkowska AB, Nandan MO, Yang VW. Notch inhibits expression of the Kruppel-like factor 4 tumor suppressor in the intestinal epithelium. Mol Cancer Res 2008;6:1920–1927. [PubMed]
20. Salam Alhasani S, Yousif NG. Critical role of IL-23 signaling in prostatic cancer. American Journal of BioMedicine 2013;1(1):58-72. [Abstract/Full-Text]
21. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, Yu Y, Cao X. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem 2009;284:16183–16190. [PubMed]
22. Giovannini C, Lacchini M, Gramantieri L, Chieco P, Bolondi L. Notch3 intracellular domain accumulates in HepG2 cell line. Anti Cancer Res 2006;26:2123–2127. [PubMed]
23. Gramantieri L, Giovannini C, Lanzi A, Chieco P, Ravaioli M, Venturi A, Grazi GL, Bolondi L. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int 2007;27:997–1007. [PubMed
24. Demarest RM, Ratti F, Capobianco AJ. It’s T-ALL about Notch. Oncogene 2008;27:5082–5091. [PubMed]
25. Shih AH, Holland EC. Notch signaling enhances nestin expression in gliomas. Neoplasia 2006;8:1072–1082. [PubMed]
26. Shiras A, Chettiar ST, Shepal V, Rajendran G, Prasad GR, Shastry P. Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells 2007;25:1478–1489. [PubMed]
27. Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 2006;106:2503–2513. [PubMed]
28. Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi’s sarcoma tumor cells. Oncogene 2005;24:6333–6344. [PubMed]
