Abstract
Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.
Highlights
Endometrial cancer is the most frequently occurring gynecologic cancer in Western countries
Effect of Metformin on the insulin-like growth factors (IGFs)-I Signaling Pathway To examine the potential regulation of the expression and activation of IGF-I receptor (IGF-insulin receptor (IR)) and downstream signaling mediators by metformin in different types of endometrial carcinoma, Type I (Ishikawa, ECC-1) and Type II (USPC-2, USPC-1) cancer cells were treated with metformin for 24 h, in the presence or absence of IGF-I during the last 10 min (Figure 1A)
Metformin down-regulated the expression of total IGF-IR and IR in USPC-2 and USPC-1 cells
Summary
Endometrial cancer is the most frequently occurring gynecologic cancer in Western countries. Endometrial cancers are classified into two major groups, with Type I being the most frequent (more than 80% of cases). Type I tumors are usually estrogen-dependent, low-grade neoplasms, with an endometroid, well-differentiated morphology, and are generally associated with a relatively good prognosis. Type II tumors are mostly diagnosed at an advanced stage, are not associated with exposure to estrogens, display a less differentiated phenotype, and have a worse prognosis. Uterine serous carcinoma (USC), which constitutes the predominant histological class among Type II tumors [2], is usually diagnosed at an advanced stage, and accounts for 50% of all relapses of the endometrial cancers, with a 5-year survival rate of 55%. The major genetic alterations that occur in Type I endometrial cancer include: microsatellite instability and mutations in the pTen, k-RAS and ß-catenin genes. Mutational analysis revealed that the USPC-2 cell line employed in the present study expresses a mutant p53 whereas USPC-1 cells express a wild type p53 (containing a number of polymorphisms) [2]. p53 is a tumor suppressor protein that regulates the expression of a wide variety of genes involved in apoptosis, growth arrest, inhibition of cell cycle progression, differentiation and accelerated DNA repair or senescence in response to genotoxic or cellular stress
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