Growth Suppression of Mouse Pituitary Corticotroph Tumor AtT20 Cells by Curcumin: A Model for Treating Cushing's Disease

effectiveness of curcumin to suppress pituitary tumorigenesis. However the molecular mechanism that mediate this effect of curcumin are still unknown.Using the mouse corticotroph tumor cells, AtT20 cells, we report that curcumin had a robust, irreversible inhibitory effect on cell proliferation and clonogenic property. The curcumin-induced growth inhibition was accompanied by decreased NFκB activity. Further, curcumin down-regulated the pro-survival protein Bcl-xL, depolarized the mitochondrial membrane, increased PARP cleavage, which led to apoptotic cell death. Finally, curcumin had a concentration-dependent suppressive effect on ACTH secretion from AtT20 cells.The ability of curcumin to inhibit NFκB and induce apoptosis in pituitary corticotroph tumor cells leads us to propose developing it as a novel therapeutic agent for the treatment of CD

Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat

OBJECTIVE - Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions. RESEARCH DESIGN AND METHODS - We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats. RESULTS - Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10-6), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation. CONCLUSIONS - Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

Expression pattern of estrogen, progesterone and HER2/neu receptors in atypical breast lesions does not predict subsequent clinically significant event

Background: While 5-year survival rates for breast cancer patients have improved, we still cannot predict whether early breast lesions, such as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH), are harbingers of future cancer. Atypia increases the risk of developing subsequent breast cancer four- to fivefold. To avoid this, women may opt for aggressive management with associated side effects. Thus, identifying predictors of future breast cancer after a diagnosis of atypia would assist in risk reduction strategy selection. Purpose: Given that lifetime estrogen exposure is a significant risk factor for breast cancer, and human epidermal growth factor receptor-2 (HER2/neu) gene amplification is linked to cancer pathogenesis, we tested whether expression patterns of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu at initial diagnosis of atypia predicted a subsequent clinically significant event (SCSE), i.e. another occurrence of atypia, in situ or invasive carcinoma. Methods: Patients with an initial diagnosis of ADH and/ or ALH were retrospectively identified. A study cohort of 19 women who developed SCSE (cases) was matched to 45 women with no SCSE for at least 5 years after atypia diagnosis (controls). Archived tissues from cases and controls were subjected to immunohistochemical analysis of ER, PR and HER2/neu. ER and PR staining patterns were reported using Allred score, while HER2/neu expression was reported as negative (0-1+), equivocal (2+) or positive (3+). Atypia with HER2/neu 2+ or 3+ scores were subject to FISH analysis to confirm gene amplification. Results: There was no significant difference in expression of ER (mean Allred score: cases = 7.26 ± 0.35; controls = 6.91 ± 0.43) or PR (mean Allred score: cases = 6.95 ± 0.43; controls = 6.57 ± 0.34). Greater than 90% of both cases and controls were negative (0-1+) for expression of HER2/neu. Longitudinal assessment of ER, PR and HER2/neu expression in the cohort of patients who developed SCSE revealed that 3 of the 19 cases presented with HER2/ neu overexpression; however FISH analysis revealed no gene amplification. Interestingly, decreased expression of ER/PR was observed in 3 of 7 patients with atypia that later developed an invasive malignancy. Conclusion: ER, PR and HER2/neu expression does not predict SCSE after an initial diagnosis of breast atypia. Although we did not detect increased expression or amplification of HER2/neu in breast atypia associated with a SCSE, the activation status of HER2/neu remains unknown

In Vitro Growth Suppression of Renal Carcinoma Cells by Curcumin

Background: Malignant clear cell renal carcinoma (ccRCC) is an aggressive tumor that is highly resistant to chemotherapy and radiation. Current therapeutic approaches to management of ccRCC have not significantly improved patient survival, therefore novel therapies are needed. The von Hippel-Lindau tumor suppressor gene is frequently mutated in ccRCC resulting in unregulated transcriptional activity of hypoxia-inducible factors (HIF) 1α and 2α. HIF-mediated transcription leads to increased growth factor expression and growth factor receptor (GFR)-mediated signaling. NFκB and STAT3 are phosphorylated in response to GFR activation and modulate gene expression, which promotes cell growth and invasion. Activated NFκB and STAT3 expression is associated with ccRCC pathogenesis. Purpose: The dietary polyphenol curcumin is a well-documented antitumor agent and a known inhibitor of NFκB and STAT3 activation. Given the lack of effective therapies that block ccRCC progression, our objective was to examine whether curcumin could suppress the growth and migration of ccRCC cells, and whether this suppression was mediated via inhibition of NFκB and STAT3 activity. Methods: Human ccRCC cell lines (769-p, 786-o, Caki-1, ACHN and A-498 cells) were exposed to curcumin to assess the impact of curcumin on ccRCC cell viability. To examine the mechanism by which curcumin induced cell death, we used 769-p cells, a highly aggressive human ccRCC cell line that does not express functional von Hippel-Lindau protein. The impact of curcumin on the phosphorylation status and transcriptional activity of NFκB and STAT3, in 769-p cells, was determined. Results: Our results show that in ccRCC cells curcumin decreased cell proliferation and cell viability, abolished clonogenic property, induced apoptosis and blocked cellular migration. The growth suppressive and proapoptotic effects of curcumin were accompanied by decreased phosphorylation and transcriptional activity of NFκB and STAT3. Conclusion: The ability of curcumin to induce apoptosis and inhibit migration of ccRCC cells justifies additional studies that explore the potential of developing curcumin or other NFκB and STAT3 inhibitors as novel therapeutic agents in the management of ccRCC