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  2. GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors

GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors

  • Neoplasia. 2024 Sep:55:101020. doi: 10.1016/j.neo.2024.101020.
Vicky Yamamoto 1 Dat P Ha 1 Ze Liu 1 Miller Huang 2 Soma Samanta 3 Nouri Neamati 3 Amy S Lee 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States.
  • 2 Department of Pediatrics, Children's Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States.
  • 3 Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States.
  • 4 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States. Electronic address: amylee@usc.edu.
Abstract

The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein. However, despite recent advances, therapeutic targeting of MYC remains challenging. Here we identify GRP78 as a new target for suppression of MYC expression. Using multiple MYC-dependent Cancer Models including head and neck squamous cell carcinoma and their cisplatin-resistant clones, breast and pancreatic adenocarcinoma, our studies revealed that GRP78 knockdown by siRNA or inhibition of its activity by small molecule inhibitors (YUM70 or HA15) reduced c-Myc expression, leading to onset of Apoptosis and loss of cell viability. This was observed in 2D Cell Culture, 3D spheroid and in xenograft models. Mechanistically, we determined that the suppression of c-Myc is at the post-transcriptional level and that YUM70 and HA15 treatment potently upregulated the eukaryotic translation inhibitor 4E-BP1, which targets eIF4E critical for c-Myc translation initiation. Furthermore, knock-down of 4E-BP1 via siRNA rescued YUM70-mediated c-Myc suppression. As YUM70 is also capable of suppressing N-MYC expression, this study offers a new approach to suppress MYC protein expression through knockdown or inhibition of GRP78.

Keywords

4E-BP1; Breast cancer; GRP78; Head and neck cancer; MYC; Pancreatic cancer; Small molecule inhibitors; YUM70.

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