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DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.

ABSTRACT: Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating the COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double-strand DNA damage or telomere malfunction results in a p53- and activin A-dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ lesions, high COX-2 expression is associated with high gammaH2AX, TRF2, activin A, and telomere malfunction. These data show that DNA damage and telomere malfunction can have both cell-autonomous and cell-nonautonomous consequences and can provide a novel mechanism for the propagation of tumorigenesis.

SUBMITTER: Fordyce C

PROVIDER: S-EPMC2954106 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.

Fordyce Colleen C Fessenden Tim T Pickering Curtis C Jung Jason J Singla Veena V Berman Hal H Tlsty Thea T

Cancer prevention research (Philadelphia, Pa.) 20091222 2

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoid ...[more]

PMID: 20028875

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Project description:Advanced age is one of the most important risk factors for osteoporosis. Accumulation of oxidative DNA damage has been proposed to contribute to age-related deregulation of osteoblastic and osteoclastic cells. Excision repair cross complementary group 1-xeroderma pigmentosum group F (ERCC1-XPF) is an evolutionarily conserved structure-specific endonuclease that is required for multiple DNA repair pathways. Inherited mutations affecting expression of ERCC1-XPF cause a severe progeroid syndrome in humans, including early onset of osteopenia and osteoporosis, or anomalies in skeletal development. Herein, we used progeroid ERCC1-XPF-deficient mice, including Ercc1-null (Ercc1(-/-)) and hypomorphic (Ercc1(-/?)) mice, to investigate the mechanism by which DNA damage leads to accelerated bone aging. Compared to their wild-type littermates, both Ercc1(-/-) and Ercc1(-/?) mice display severe, progressive osteoporosis caused by reduced bone formation and enhanced osteoclastogenesis. ERCC1 deficiency leads to atrophy of osteoblastic progenitors in the bone marrow stromal cell (BMSC) population. There is increased cellular senescence of BMSCs and osteoblastic cells, as characterized by reduced proliferation, accumulation of DNA damage, and a senescence-associated secretory phenotype (SASP). This leads to enhanced secretion of inflammatory cytokines known to drive osteoclastogenesis, such as interleukin-6 (IL-6), tumor necrosis factor ? (TNF?), and receptor activator of NF-?B ligand (RANKL), and thereby induces an inflammatory bone microenvironment favoring osteoclastogenesis. Furthermore, we found that the transcription factor NF-?B is activated in osteoblastic and osteoclastic cells of the Ercc1 mutant mice. Importantly, we demonstrated that haploinsufficiency of the p65 NF-?B subunit partially rescued the osteoporosis phenotype of Ercc1(-/?) mice. Finally, pharmacological inhibition of the NF-?B signaling via an I-?B kinase (IKK) inhibitor reversed cellular senescence and SASP in Ercc1(-/?) BMSCs. These results demonstrate that DNA damage drives osteoporosis through an NF-?B-dependent mechanism. Therefore, the NF-?B pathway represents a novel therapeutic target to treat aging-related bone disease.

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DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.

Publications

DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.

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