The role of Endoplasmic Reticulum stress and GRP78 in endometrial cancer

Abstract

Endometrial cancer is the most common malignancy of the female genital tract. However, in spite of a huge advance in our understanding of endometrial cancer biology, therapeutic modalities haven't significantly changed over the past 40 years. Recent studies have indicated that endoplasmic reticulum stress, the unfolded protein response activation and altered GRP78 expression can play an important role in a variety of tumors development and progression. Our previous studies reported for the first time that GRP78 is increased in endometrial tumors. In this study, we further analyzed the role of UPR and GRP78 in endometrial cancer progression. We found that GRP78 plays a role in endometrial cancer progression since its silencing attenuate both the growth and invasion of endometrial cancer cells. Interestingly, we also show that metformin, an antidiabetic drug with anticancer properties, is able to inhibit endometrial cancer cells growth and this is accompanied by the inhibition of GRP78 expression and upregulation of proapoptotic UPR genes such as ATF4 and CHOP. Finally, we describe that metformin affects β-catenin signaling, a frequently activated signaling pathway in endometrial cancer. These observations highlight the possibility that GRP78 might represent an intriguing therapeutic target of metformin action in the treatment of endometrial cancer.