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Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.

ABSTRACT: Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We showed previously that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpressed in human leiomyosarcomas, a highly malignant uterine cancer. Although epidemiologic studies indicate that individuals who take COX inhibitors have a lower incidence of some tumors, these inhibitors have not been evaluated in uterine cancer. Here, we show that HMGA1a mice on sulindac (a COX-1/COX-2 inhibitor) have significantly smaller uterine tumors than controls. To determine if COX inhibitors are active in human uterine cancers that overexpress HMGA1a, we treated cultured cells with sulindac sulfide or celecoxib (a specific COX-2 inhibitor). Both drugs block anchorage-independent growth in high-grade human uterine cancer cells that overexpress HMGA1a (MES-SA cells). In contrast, neither inhibitor blocked transformation in cells that do not overexpress HMGA1a. Moreover, xenograft tumors from MES-SA cells were significantly inhibited in mice on sulindac. More strikingly, no tumors formed in mice on celecoxib. These preclinical studies suggest that COX inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway. Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced-stage uterine cancers.

SUBMITTER: Di Cello F

PROVIDER: S-EPMC2593419 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.

Di Cello Francescopaolo F Hillion Joelle J Kowalski Jeanne J Ronnett Brigitte M BM Aderinto Abimbola A Huso David L DL Resar Linda M S LM

Molecular cancer therapeutics 20080701 7

Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We showed previously that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpresse ...[more]

PMID: 18645019

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Project description:Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the ras oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peritumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of nontransgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 autodetected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio| > = 1.5, p < = 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared with Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared with that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the upregulated proteins in T compared with Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatocytes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.

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Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.

Publications

Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.

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