GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors
The 78-kDa glucose-regulated protein (GRP78), frequently upregulated in various tumors, serves as an important prognostic marker and a promising therapeutic target for inhibiting tumorigenesis and overcoming treatment resistance. While GRP78 is well known as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic functions and as a central regulator of the unfolded protein response, its emerging role in regulating oncoprotein expression has garnered increasing attention. MYC, which is dysregulated in approximately 70% of human cancers, is one of the most commonly activated oncoproteins. However, targeting MYC therapeutically remains a significant challenge.
In this study, we identify GRP78 as a novel target for suppressing MYC expression. Using multiple MYC-dependent cancer models, including head and neck squamous cell carcinoma and their cisplatin-resistant clones, as well as breast and pancreatic adenocarcinomas, we demonstrate that knockdown of GRP78 via siRNA or inhibition of its activity by small molecule inhibitors (YUM70 or HA15) significantly reduces c-MYC expression. This reduction in c-MYC leads to the induction of apoptosis and a loss of cell viability, which we observed in 2D cell cultures, 3D spheroid models, and in xenograft models.
Mechanistically, we found that the suppression of c-MYC occurs at the post-transcriptional level, with treatment by YUM70 and HA15 leading to a potent upregulation of the eukaryotic translation inhibitor 4E-BP1. This protein targets eIF4E, a critical factor for initiating c-MYC translation. Furthermore, knockdown of 4E-BP1 using siRNA rescued c-MYC suppression induced by YUM70. Notably, YUM70 also suppressed N-MYC expression, highlighting its potential to target both MYC isoforms.
This study reveals a novel approach to suppress MYC protein expression by targeting GRP78, providing a potential therapeutic strategy for MYC-driven cancers.