Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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OBJECTIVENew-onset diabetes mellitus (DM) in elderly patients is associated with increased risk of diabetes complications and mortality. It is unknown whether glycemic control in this population influences the mortality risk.RESEARCH DESIGN AND METHODSThe current study was conducted using the computerized database of the Sharon-Shomron District of Clalit Health Services in Israel. Included in the study were subjects 65 years of age and above with new-onset DM. The primary outcome measures were all-cause mortality and coronary revascularization procedures with either percutaneous coronary intervention or coronary artery bypass grafting.RESULTSParticipants (n = 2,994) were stratified into four groups according to their mean HbA1c levels during the follow-up period (<6.5% [48 mmol/mol], 6.5–6.99% [48–52 mmol/mol], 7–7.49% [53–57 mmol/mol], and ≥7.5% [58 mmol/mol]). During a mean follow-up of 5.54 ± 2.1 years, 1,173 (39.17%) participants died and 285 (9.51%) underwent coronary revascularization. An HbA1c level >7.5% (58 mmol/mol) was associated with a significantly increased all-cause mortality rate (hazard ratio [HR] 1.74 [95% CI 1.2–1.8], P < 0.0001). This difference remained statistically significant after a multivariate model adjusted for the conventional cardiovascular risk factors and for the use of hypoglycemic agents and statins. Kaplan-Meier survival plots revealed lower survival rates in this group of patients. Coronary revascularization rates were highest among subjects with HbA1c 6.5–6.99% (48–52 mmol/mol) (HR 1.6 [1.01–2.4], P < 0.05) and lowest in patients with HbA1c ≥7.5% (58 mmol/mol).CONCLUSIONSAn HbA1c level >7.5% (58 mmol/mol) is associated with increased risk for all-cause mortality and with a lower revascularization rate in elderly patients with new-onset DM.