title: Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation.
abstract: Cell cycle re-entry by quiescent cancer cells is an important mechanism for cancer progression. While high levels of c-MYC expression are sufficient for cell cycle re-entry, the modality to block c-MYC expression, and subsequent cell cycle re-entry, is limited. Using reversible quiescence rendered by serum withdrawal or contact inhibition in PTEN(null)/p53(WT) (LNCaP) or PTEN(null)/p53(mut) (PC-3) prostate cancer cells, we have identified a compound that is able to impede cell cycle re-entry through c-MYC. Guttiferone K (GUTK) blocked resumption of DNA synthesis and preserved the cell cycle phase characteristics of quiescent cells after release from the quiescence. In vehicle-treated cells, there was a rapid increase in c-MYC protein levels upon release from the quiescence. However, this increase was inhibited in the presence of GUTK with an associated acceleration in c-MYC protein degradation. The inhibitory effect of GUTK on cell cycle re-entry was significantly reduced in cells overexpressing c-MYC. The protein level of FBXW7, a subunit of E3 ubiquitin ligase responsible for degradation of c-MYC, was reduced upon the release from the quiescence. In contrast, GUTK stabilized FBXW7 protein levels during release from the quiescence. The critical role of FBXW7 was confirmed using siRNA knockdown, which impaired the inhibitory effect of GUTK on c-MYC protein levels and cell cycle re-entry. Administration of GUTK, either in vitro prior to transplantation or in vivo, suppressed the growth of quiescent prostate cancer cell xenografts. Furthermore, elevation of FBXW7 protein levels and reduction of c-MYC protein levels were found in the xenografts of GUTK-treated compared with vehicle-treated mice. Hence, we have identified a compound that is capable of impeding cell cycle re-entry by quiescent PTEN(null)/p53(WT) and PTEN(null)/p53(mut) prostate cancer cells likely by promoting c-MYC protein degradation through stabilization of FBXW7. Its usage as a clinical modality to prevent prostate cancer progression should be further evaluated.
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xi
authors.affiliation: Discipline of Endocrinology, Royal Prince Alfred Hospital and Charles Perkins Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Discipline of Endocrinology, Royal Prince Alfred Hospital and Charles Perkins Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|School of Science and Health, The University of Western Sydney, Penrith South, Sydney, NSW, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Xie
authors.affiliation: Origins of Cancer Program, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: J
authors.identifier: 0000-0002-0377-9318
authors.initials: J
authors.lastname: Holst
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Sydney, NSW, Australia.|School of Women's and Children's Health, UNSW Medicine, Sydney, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lao
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Tan
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
authors.forename: H-X
authors.initials: HX
authors.lastname: Xu
authors.affiliation: Discipline of Endocrinology, Royal Prince Alfred Hospital and Charles Perkins Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|School of Science and Health, The University of Western Sydney, Penrith South, Sydney, NSW, Australia.
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D055785:Gene Knockdown Techniques; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D001577:Benzophenones; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016271:Proto-Oncogene Proteins c-myc; D025801:Ubiquitin; C519762:guttiferone K; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex