Focusing Downstream in Lung Cancer Prevention: 15-Hydroxyprostaglandin Dehydrogenase

Perspective

Steven M. Dubinett, Jenny T. Mao and Saswati Hazra

Deregulated inflammatory mediators and growth factors lung cancer environment. This leads to enhanced production seem to act in concert with mutational events in driving ma- of deleterious PG products, including prostaglandin E2 lignant transformation and progression, thus contributing to (PGE2), which has well-established protumorigenic effects. the complex pulmonary environment in the lung at risk for Contributors to persistent elevation of COX-2 in epithelial cancer. Pulmonary diseases that are associated with the great- stromal and lung cancer cells include cytokines such as in- est risk for malignancy are characterized by abundant and de- terleukin (IL)-1β and transforming growth factor β, growth regulated inflammation (1). Profound abnormalities in factors including epidermal growth factor, oncogenic events inflammatory-fibrotic pathways evident in chronic obstructive such as mutant Kras or loss of p53, hypoxia, and tobacco- pulmonary disease/emphysema, pulmonary fibrosis, and specific carcinogens (6–9). Once COX-2 is up-regulated in other pulmonary disorders continue in exaggerated fashion lung cancer cells, its elevation may be maintained by ab- in the setting of established lung cancer (2). For example, the normalities in signaling pathways required to down-regulate procarcinogenic prostaglandins (PG), which are released in COX-2. Two such abnormalities are loss of IL-10 receptor these settings, contribute to the aberrant production of cyto- expression and constitutive nuclear localization of signal kines and growth factors. This finding led to the research fo- transducers and activators of transcription 6 (10, 11). Che- cus on cyclooxygenase (COX; also referred to as PG motherapy including taxanes also can stabilize COX-2 endoperoxidase or PGG hydroperoxide synthase), the rate- mRNA, thus leading to its prolonged and unregulated ex- limiting enzyme for the production of PGs and thromboxanes pression (12). from free arachidonic acid released from membrane phospho- In lung cancer development and progression, elevations of lipids by phospholipase A2 (3). COX-2 and PGE2 are driving forces for the hallmarks of ma- Two COX isoforms, COX-1 and COX-2, have been studied lignancy including apoptosis resistance (13), proliferation extensively. COX-1 is constitutively expressed in most cells (14), immunosuppression (15), angiogenesis (16), invasion and tissues. The inducible isoenzyme COX-2 is an immediate (17), and epithelial-mesenchymal transition (18). These find- early response gene expressed following exposure to cyto- ings led to lung cancer chemoprevention trials using COX-2 kines, growth factors, and other stimuli, thus enhancing inhibitors. Although some encouraging preliminary results eicosanoid production during inflammation. COXs are bi- are available from these trials (19, 20), several problems with functional enzymes, with fatty acid COX activity and PG hy- COX-2 inhibitors likely will limit their widespread use in droperoxidase activity ultimately producing PGH2 (4). PGH2 cancer chemoprevention. First, the potential risk of cardio- is converted to a variety of eicosanoids by individual PG vascular toxicities associated with the long-term use of synthases that are often expressed in a cell type–dependent COX-2 inhibitors may prove to be prohibitive for many indi- manner. The COX isoforms share the same structural features viduals in the setting of chemoprevention. Second, in addi- including a hydrophobic channel that allows arachidonic tion to inhibiting PGE2 production, the upstream blockade acid to access the COX catalytic site (5). Therefore, relative of COX-2 has the capacity to decrease PGs such as PGI2 production of the various COX products depends on the and PGD2 that have been found to have antitumor properties cellular concentrations of COX enzymes as well as down- (21). Similarly, the inhibition of COX-2 could result in in- stream metabolic and catabolic enzymes within the COX creases in leukotrienes that have protumorigenic capacity pathway. (22). In some settings, therefore, the sword of COX-2 inhi- Whereas the COX enzymes are expressed at low constitu- bition may be too blunt to specifically attack the tumor- tive levels in the normal lung, a variety of factors may con- promoting activities of the arachidonic acid pathway, and tribute to the up-regulation of COX-2 in the developing new approaches will be required to target the pathway downstream of COX-2 for lung cancer prevention. Instead of directly inhibiting COX-2, it has been suggested that hitting downstream targets in the COX pathway may be more effective and less toxic for lung cancer chemoprevention Authors'Affiliation: Division of Pulmonary and Critical Care Medicine, UCLA Lung Cancer Research Program, Johnsson Comprehensive Cancer Center, (23). One downstream opportunity involves targeting the re- David Geffen School of Medicine at University of California, Los Angeles, Los ceptors whereby PGE2 mediates its tumor-promoting effects. Angeles, California – PGE2 exerts its multiple effects through four G-protein Received 07/16/2008; accepted 07/28/2008. Requests for reprints: Steven M. Dubinett, Division of Pulmonary and Cri- coupled receptors, designated as E-type PG (EP)receptors 1 tical Care Medicine, David Geffen School of Medicine at University of California, through 4 (24). Response to PGE2 depends on the concentra- Los Angeles, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095- tion and distribution of cell-surface EP receptors. The EP1 re- 1690. Phone: 310-794-6566; Fax: 310-267-2829; E-mail: sdubinett@mednet. ceptor acts via G protein to increase cellular Ca2+ level. EP2 ucla.edu. q ©2008 American Association for Cancer Research. and EP4 receptor signaling is mediated by Gs proteins that ac- doi:10.1158/1940-6207.CAPR-08-0148 tivate adenylate cyclase and elevate cyclic AMP synthesis. In

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contrast, EP3 receptor signaling through Gi inhibits adenylate donic acid pathway in the context of lung cancer cyclase and cyclic AMP synthesis (24). prevention. Targeted intervention that promotes the degra- Studies suggest that PGE2 mediates lung cancer invasive- dation of the procarcinogenic PGs including PGE2 could ness through EP4 receptor signaling and that genetic inhibi- lead to a more favorable pulmonary environment in the tion of tumor COX-2 leads to diminished invasion, likely lung at risk for carcinogenesis. Elevating 15-PGDH could in- due to reduced expression of matrix metalloproteinase-2, crease the ratio of antitumorigenic to procarcinogenic PGs. CD44, and EP4 receptor (17). These findings indicate that For example, a decline in PGE2 without alteration of PGI2 – PGE2 regulates COX-2 dependent CD44 and matrix metallo- levels could favor antitumorigenic effects as well as limit proteinase-2–mediated invasion in lung cancer via EP receptor cardiovascular toxicities that might be associated with signaling (17). In a murine model, Yang et al. (25) revealed that COX-2 inhibitors. tumor metastasis to the lung was significantly reduced by Recent reports help explain decreased 15-PGDH in breast treatment with a specific EP4 antagonist or when EP4 receptor and lung cancers. Wolf et al. (29)reported that 15-PGDH is expression was knocked down (via RNA interference)in epigenetically silenced in breast cancer, and Yang et al. (34) tumor cells. In addition, metastasis and tumor growth are re- found that Zeb1 and Slug, members of the zinc-finger E-box- duced in EP4 receptor knockout animals (25). The prolifera- binding transcriptional repressor family, repress 15-PGDH tion of human lung carcinoma cells following stimulation promoter activity in NSCLC. The latter finding is particu- of the EP4 receptor provides further evidence of the role of larly interesting because mediators of inflammation includ- β E-type prostanoid receptors in lung carcinogenesis (26). ing IL-1 and PGE2 have recently been found to induce Although blocking PGE2 activity by targeting the EP4 receptor the expression of certain members of this family of transcrip- was effective in these preclinical models, studies also reveal tional repressors including Snail, Slug, and Zeb-1 (18, 35). that different EP receptor subtypes may mediate different This suggests that inflammatory mediators known to be malignant phenotypes. For example, lung cancer invasion abundant in the at-risk lung may contribute to the suppres- may be mediated by the EP4 receptor whereas the prolifera- sion of 15-PGDH. Furthermore, because PGE2 has the capa- tive response may be promoted by EP1 receptor signaling city to promote these transcriptional repressors, which then (27). Defining the contribution of the EP receptors in mediat- decrease 15-PGDH, a procarcinogenic self-enhancing process ing procarcinogenic events will require further investigations could be operative in the developing lung tumor environ- in model systems relevant to chemoprevention. ment. The capacity for cytokines such as IL-1β to induce Another opportunity to suppress lung carcinogenesis via membrane PGE synthase 1 could also contribute to these targets downstream of COX-2 is to promote increased PGE2 effects (36). metabolism and clearance. The catabolic enzyme 15-hydroxy- Although mutations in hydroxyprostaglandin dehydrogen- prostaglandin dehydrogenase (15-PGDH), recently identified ase (HPGD; encoding 15-PGDH)have not been described in to have tumor suppressor activity (28, 29), converts PGE2 to lung cancer, a recent report by Uppal et al. (37)describes inactive 15-keto derivatives (30). Although the 15-keto deriva- HPGD mutations in primary (idiopathic)hypertrophic os- tives are not active in mediating EP receptor–dependent sig- teoarthropy. These mutations led to decreased 15-PGDH naling, they have recently been reported to have peroxisome activity and increased systemic PGE2. Although not studied proliferator-activated receptor-γ ligand activity and therefore by Uppal et al., the common secondary form of this disease, could promote antitumor responses (31). Preventing the ex- often referred to as pulmonary hypertrophic osteoarthropy pression of 15-PGDH limits the degradation of PGE2, allowing including digital clubbing, is closely associated with pul- it to accumulate and thus encouraging tumor growth (28). monary diseases and intrathoracic malignancies. Further Therefore, augmenting 15-PGDH expression could lower studies will be required to determine if pulmonary hyper- PGE2 concentrations and carcinogenic effects in the develop- trophic osteoarthropy is associated with decreased 15-PGDH ing tumor microenvironment. due to either HPGD mutations or epigenetic silencing. The In this issue of the journal, Hughes et al. (32)contribute im- normal lung seems to be the major site of 15-PGDH activity portant new information in their report “NAD+-Dependent and therefore PG deactivation (38). Therefore, pulmonary 15-Hydroxyprostaglandin Dehydrogenase Regulates Levels diseases, including those with the greatest risk for lung – ” of Bioactive Lipids in Non Small-Cell Lung Cancer. They cancer, may have limitations in their capacity for PGE2 found that 15-PGDH is commonly down-regulated in non– deactivation (39, 40). Additional research will be required small-cell lung cancer (NSCLC)relative to normal lung, an ef- to determine if this particular potential pulmonary “insuffi- fect that contributes to the accumulation of procarcinogenic ciency” exacerbates the problem of the overproduction of PGs in NSCLC. The strength of these findings is the use of PGE2 in at-risk lung tissue. humantissuesandcorroborationincomplementaryin vitro Because 15-PGDH has been described as having tumor sup- and in vivo studies documenting that the enhanced levels pressor activities in lung cancer (28, 41), investigators have of procarcinogenic PGs in NSCLC are a consequence of down- asked if the levels and/or activity of 15-PGDH can be manipu- regulation of 15-PGDH. Recent studies corroborate the lated pharmacologically. Recent studies indicate that histone importance of these findings. Huang et al. (33)found that deacetylase inhibitors (42), steroids (41), epidermal growth the forkhead transcription factor hepatocyte nuclear factor factor receptor inhibitors (34), and thiazolidinediones (43) 3β is a potent transcriptional inducer of 15-PGDH, which have the capacity to increase 15-PGDH. Although all of these showed tumor suppressor and antiangiogenic functions agents are being considered for lung cancer chemoprevention, in vivo. developmental work is still needed, including studies to de- The findings of Hughes et al. provide further strong jus- fine subgroups of at-risk individuals and to develop preven- tification to pursue a novel avenue for attacking the arachi- tive agents targeting this pathway.

Cancer Prev Res 2008;1(4) September 2008 224 www.aacrjournals.org

Understanding the events downstream of COX-2 in of the downstream events and the complexities of pul- the arachidonic acid pathway in the context of pulmonary monary carcinogenesis and provides new insights for future carcinogenesis will facilitate new opportunities for targeted chemoprevention. intervention. For example, additional downstream targets, including the recently described PG transporters in colon cancer, may also be discovered to be operational in the Disclosure of Potential Conflicts of Interest pathogenesis of lung cancer (44). The work of Hughes S. Dubinett serves on the scientific advisory board for Tragara Pharmaceu- et al. (32)is a significant contribution to our understanding ticals.

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Steven M. Dubinett,, Jenny T. Mao and Saswati Hazra

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