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JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice.

ABSTRACT: Our previous studies indicated that JWA plays an important role in DNA damage repair, cell migration, and regulation of MAPKs. In this study, we investigated the role of JWA in chemical carcinogenesis using conditional JWA knockout (JWA(?2/?2)) mice and two-stage model of skin carcinogenesis. Our results indicated that JWA(?2/?2) mice were resistant to the development of skin papillomas initiated by 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In JWA(?2/?2) mice, the induction of papilloma was delayed, and the tumor number and size were reduced. In primary keratinocytes from JWA(?2/?2) mice, DMBA exposure induced more intensive DNA damage, while TPA-promoted cell proliferation was reduced. The further mechanistic studies showed that JWA deficiency blocked TPA-induced activation of MAPKs and its downstream transcription factor Elk1 both in vitro and in vivo. JWA(?2/?2) mice are resistance to tumorigenesis induced by DMBA/TPA probably through inhibition of transcription factor Elk1 via MAPKs. These results highlight the importance of JWA in skin homeostasis and in the process of skin tumor development.

SUBMITTER: Gong Z

PROVIDER: S-EPMC3312911 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice.

Gong Zhenghua Z Shi Yaowei Y Zhu Ze Z Li Xuan X Ye Yang Y Zhang Jianbing J Li Aiping A Li Gang G Zhou Jianwei J

PloS one 20120326 3

Our previous studies indicated that JWA plays an important role in DNA damage repair, cell migration, and regulation of MAPKs. In this study, we investigated the role of JWA in chemical carcinogenesis using conditional JWA knockout (JWA(Δ2/Δ2)) mice and two-stage model of skin carcinogenesis. Our results indicated that JWA(Δ2/Δ2) mice were resistant to the development of skin papillomas initiated by 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-ac ...[more]

PMID: 22461904

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Project description:The heterotrimeric G protein α subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of GNAQ/11(Q209L) in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling. Here, using mouse melanocyte cell graft tumorigenesis models, we determined that Ric-8A genetic ablation attenuated the abundance and melanoma-driving potential of Gαq-Q209L. A new conditional Ric-8A(Flox/Flox); Rosa-CreER(+/)(-) mouse strain was derived and used as a tissue source to culture an immortalized, tamoxifen-inducible Ric-8A knockout melanocyte cell line that required 12-O-tetradecanoylphorbol-13-acetate (TPA, phorbol ester) for growth. The cell line failed to grow tumors when grafted into immune-compromised mice regardless of Ric-8A expression. Stable expression of human GNAQ(Q209L), but not GNAQ(WT) in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors. Deletion of Ric-8A in GNAQ(Q209L) cells restored TPA-dependent growth, reduced Gαq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts. Interestingly, TPA treatment of cultured GNAQ(Q209L) cells or host animals grafted with GNAQ(Q209L) cells also sharply reduced Gαq-Q209L abundance and tumorigenic capacity. Finally, tumorigenesis initiated from GNAQ(Q209L) cell grafts, followed by host mouse systemic tamoxifen treatment to delete Ric-8A in the grafted cells completely abrogated GNAQ(Q209L)-driven tumor progression unless a stable human RIC-8A transgene was used to rescue the floxed Ric-8A alleles. Our work defines two new rational targets that may be developed as potential uveal melanoma therapies through reduction of Gαq/11-Q209L oncoprotein abundance: (1) Ric-8A inhibition and (2) phorbol ester treatment.

Project description:BackgroundBreast cancer (BC), because of its invasive characteristics, is one of the most common and deadliest cancers among the female population around the world. Research has demonstrated that AhR signaling also plays a vital role in BC initiation and development as well. Therefore, blocking this pathway to natural interferences paves a new channel for the prevention of BC. Several natural compounds such as flavonoids possess the anticancer activities against different cancers.ObjectiveThe present study has been designed to estimate the chemotherapeutic potential of taxifolin (TAX) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in Sprague-Dawley rats.Materials and methodsInitially, the molecular docking analysis of AhR and cytochrome P450s (CYPs) (CYP1A1 and CYP1B1) was performed using MAESTRO tool, in an attempt to rationalize the activity of TAX, based on their CYP1-binding potential. The in vitro CYP1A1 activity was determined by luciferase assay with CYP1A1 substrate luciferin CEE. The in vivo analysis was performed by administrating TAX at 10, 20, 40 mg/kg BW for 28 days intragastrically in DMBA induced (25 mg/animal dose) at 55 days of age Sprague-Dawley (SD) rats. BC initiates after 90 days of tumor induction phase. The molecular mechanism of TAX on Ahr and CYPs was also examined through the mRNA and protein expressions using reverse transcription-quantitative polymerase chain reaction and Western blotting analysis.ResultsFurthermore, TAX altered the energy regulation on DMBA-induced BC in SD rats by considerably restoring the cancer-induced modulations in tumor growth. Our results showed that TAX reduced the expressions of CYP1A1 and CYP1B1 in DMBA-induced mammary carcinoma by downregulating the AhR signaling pathway.ConclusionThis study revealed that TAX might be able to act as a chemotherapeutic agent against CYP1A1- and CYP1B1-mediated cancer and the inhibition of the DMBA-induced mammary carcinogenesis in a rat model.Abbreviations used: CYPs: Cytochrome P450s; PAH: polycyclic aromatic hydrocarbons; HRP- Horseradish peroxidase; BSA: Bovine serum albumin; DTTP: Deoxythymidine Triphosphate (nucleotide); RT-qPCR: Real Time quantitative polymerase chain reaction; CADD: Computer Aided Drug Drafting.

Dataset Information

JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice.

Publications

JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice.

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