Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2 À/À ) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth. [Cancer Res 2007;67(22):10804-12]

Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an ''insulin sensitizer'' because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformininduced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.

A new approach to treating urodynamic stress incontinence (USI) is the transobturator tension-free vaginal tape (TOT). Inserting a suburethral tape at the mid-urethral level by the perineal route provides a minimally invasive means of reinforcing the structures that support the urethra. This approach, first described as the tension-free vaginal tape procedure, makes it unnecessary to gain blind entry into the retropubic space with the attendant risks of injuring the bladder, bowel, major blood vessels, or nerves.This retrospective cohort study was planned to determine the frequency of-and risk factors for-lower urinary tract (LUT) injuries in 389 women who, in the years 2002-2006, had a TOT procedure as treatment for USI at a tertiary referral urogynecology center. The outside-in technique was used in 241 cases, most often with Obtape®, while the remaining 148 women were operated on using the inside-out technique. In 70% of cases, the TOT procedure was primary surgery for USI. In 111 cases, another surgical procedure was carried out at the same time.Four LUT injuries were documented, 2 affecting the urethra and 2 the bladder. All 4 women had surgery using the outside-in technique, but this was not a statistically significant finding. Three of the 4 women with injuries underwent another procedure involving colporrhaphy. Both women with urethral injury underwent TOT surgery as a secondary procedure. In contrast, both those with bladder injuries were undergoing primary continence surgery. The overall incidence of LUT injury in this series was 1%.LUT injury is an infrequent complication of TOT procedures. In the present series of nearly 400 women, LUT injuries occurred only when using the outside-in technique. Intraoperative cystoscopy should be considered in selected cases only, but postoperative problems such as hematuria call for immediate cystoscopy. GYNECOLOGY Volume 62, Number 3 OBSTETRICAL AND GYNECOLOGICAL SURVEY ABSTRACTThe inability of colposcopy to reliably rule out cervical intraepithelial neoplasia (CIN) 2 or more advanced changes has complicated the management of women diagnosed colposcopically as having human papillomavirus (HPV) or CIN 1. This study assessed the risk of CIN 3 or cancer in a group of women given a colposcopic diagnosis of CIN 1 or less. The participants, with no past history of CIN, underwent colposcopy to evaluate abnormal cervical cytology in the form of atypical Office Gynecology 173 174 Obstetrical and Gynecological Survey Office Gynecology 175 176 Obstetrical and Gynecological Survey ABSTRACTMore than 10% of epithelial ovarian neoplasms are borderline ovarian tumors (BOTS), also known as ovarian tumors of low malignant potential. About one-fourth of them are found in potentially fertile women. Once thought to be a precursor of epithelial ovarian cancer, the BOT now is viewed as a biologically distinct entity. Five-year survival rates exceeding 95% are reported. Among 101 women operated on for BOT in the years 1992-2001 were 22 who had a fertility-preserving procedure in which at l...

Population studies provide evidence that obesity and insulin resistance are associated not only with elevated serum insulin levels and reduced serum adiponectin levels but also with increased risk of aggressive prostate and colon cancer. We show here that adiponectin activates AMP-activated protein kinase (AMPK) in colon (HT-29) and prostate (PC-3) cancer cells. These results are consistent with prior observations in myocytes, but we show that in epithelial cancer cells AMPK activation is associated with reduction in mammalian target of rapamycin activation as estimated by Ser 2448 phosphorylation, with reduction in p70S6 kinase activation as estimated by Thr 389 phosphorylation, with ribosomal protein S6 activation as estimated by Ser 235/236 phosphorylation, with reduction in protein translation as estimated by [ 35 S]methionine incorporation, and with growth inhibition. Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. Thus, adiponectin has the characteristics of a AMPK-dependent growth inhibitor that is deficient in obesity, and this may contribute to the adverse effects of obesity on neoplastic disease. Furthermore, metformin was observed to activate AMPK and to have growth inhibitory actions on prostate and colon cancer cells, suggesting that this compound may be of particular value in attenuating the adverse effects of obesity on neoplasia.