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http://dx.doi.org/10.47853/FAS.2021.e1

Aspergillus fumigatus-derived demethoxyfumitremorgin C inhibits proliferation of PC3 human prostate cancer cells through p53/p21-dependent G1 arrest and apoptosis induction  

Kim, Young-Sang (Department of Chemistry, Pukyong National University)
Park, Sun Joo (Department of Chemistry, Pukyong National University)
Publication Information
Fisheries and Aquatic Sciences / v.24, no.1, 2021 , pp. 1-9 More about this Journal
Abstract
Human prostate cancer is the second most frequently diagnosed cancer worldwide, and its incidence rate continues to increase. Advanced prostate cancer is more difficult to treat than early forms due to its chemotherapy resistance. There is need for more effective agents that can inhibit the progression of advanced prostate cancer. Demethoxyfumitremorgin C (DMFTC) was isolated from the fermentation extract of the marine fungus Aspergillus fumigatus. Antiproliferative activity of DMFTC against human prostate cancer PC3 cells was examined through cell cycle analysis by flow cytometry, the fluorescent nuclear imaging analysis with propidium iodide (PI), and proteins expression related to cell cycle arrest and apoptosis were investigated via Western blotting. DMFTC inhibited PC3 cells growth through G1 phase cell cycle arrest and apoptosis induction. It activated the tumor suppressor p53 and the Cdk inhibitor p21, which regulate the cell progression into the G1 phase. Additionally, PI-positive late apoptotic non-viable cells were increased and the expression levels of the G1-positive downstream regulators cyclin D, cyclin E, Cdk2, and Cdk4 were decreased by DMFTC treatment. These results suggest that DMFTC induces G1 arrest and apoptosis induction through regulation of p53/p21-dependent cyclin-Cdk complexes, and it may be a useful therapeutic agent for the treatment of human advanced prostate cancer.
Keywords
Demethoxyfumitremorgin C; Aspergillus fumigates; Prostate cancer; G1 cell cycle arrest; Cell death;
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1 Lee DH, Szczepanski M, Lee YJ. Role of Bax in quercetin-induced apoptosis in human prostate cancer cells. Biochem Pharmacol. 2008;75:2345-55.   DOI
2 Li YX, Kang KH, Kim HJ, Kim SK. In vitro induction of apoptosis by isosclerone from marine-derived fungus Aspergillus fumigatus. Bioorg Med Chem Lett. 2014;24:3923-7.   DOI
3 Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med. 2002;346:1963-9.   DOI
4 Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491-4.
5 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. 2002;90:162-73.   DOI
6 Sherr CJ. Cancer cell cycles. Science. 1996;274:1672-7.   DOI
7 Yin XY, Grove L, Datta NS, Long MW, Prochownik EV. C-myc overexpression and p53 loss cooperate to promote genomic instability. Oncogene. 1999;18:1177-84.   DOI
8 Pilat MJ, Kamradt JM, Pienta KJ. Hormone resistance in prostate cancer. Cancer Metastasis Rev. 1998;17:373-81.   DOI
9 Kyprianou N, Tu H, Jacobs SC. Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum Pathol. 1996;27:668-75.   DOI
10 Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992;70:923-35.   DOI
11 Swathi J, Narendra K, Sowjanya K, Satya AK. Marine fungal metabolites as a rich source of bioactive compounds. African J Biochem Res. 2013;7:184-96.   DOI
12 Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011;12:245-55.   DOI
13 Baade PD, Youlden DR, Krnjacki LJ. International epidemiology of prostate cancer: geographical distribution and secular trends. Mol Nutr Food Res. 2009;53:171-84.   DOI
14 Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993;362:849-52.   DOI
15 Cui CB, Kakeya H, Osada H. Novel mammalian cell cycle inhibitors, cyclotroprostatins A-D, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron. 1997;53:59-72.   DOI
16 Finefield JM, Frisvad JC, Sherman DH, Williams RM. Fungal origins of the bicyclo[2,2,2]diazaoctane ring system of prenylated indole alkaloids. J Nat Prod. 2012;75:812-33.   DOI
17 Karnak D, Xu L. Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Curr Drug Targets. 2010;11:699-707.   DOI
18 Ben-Ami R, Lewis RE, Leventakos K, Kontoyiannis DP. Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites. Blood. 2009;114:5393-9.   DOI
19 Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-607.   DOI
20 Cui CB, Kakeya H, Okada G, Onose R, Osada H. Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. I. taxonomy, fermentation, isolation and biological properties. J Antibiot. 1996;49:527-33.   DOI
21 Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8:2540-51.   DOI
22 Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys. 2003;410:177-85.   DOI
23 Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-25.   DOI
24 Killough JH, Magill GB, Smith RC. The treatment of amebiasis with fumagillin. Science. 1952;115:71-2.   DOI
25 Kim YS, Kim SK, Park SJ. Apoptotic effect of demethoxyfumitremorgin C from marine fungus Aspergillus fumigatus on PC3 human prostate cancer cells. Chem Biol Interact. 2017;269:18-24.   DOI
26 Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002;8:282-8.   DOI