The role of Endoplasmic Reticulum stress and GRP78 in endometrial cancer

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

Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism

Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer