2. Academic Validation
  3. Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19

Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19

  • Cell Biosci. 2024 Sep 6;14(1):115. doi: 10.1186/s13578-024-01297-3.
Dat P Ha # 1 2,  Woo-Jin Shin # 3 4,  Ze Liu # 1 2,  Michael E Doche 5,  Roy Lau 5,  Nektaria Maria Leli 6,  Crystal S Conn 6,  Mariangela Russo 7,  Annalisa Lorenzato 7,  Constantinos Koumenis 6,  Min Yu 2 8,  Shannon M Mumenthaler 2 5 9,  Amy S Lee 10 11
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 2 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 3 Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL, 34987, USA.
  • 4 Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA.
  • 5 Ellison Institute of Technology, Los Angeles, CA, 90064, USA.
  • 6 Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 7 Dipartimento di Oncologia, Molecular Biotechnology Center, Università di Torino, Turin, Italy.
  • 8 Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 9 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 10 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. amylee@usc.edu.
  • 11 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. amylee@usc.edu.
  • # Contributed equally.
PMID: 39238058 DOI: 10.1186/s13578-024-01297-3
Abstract

Background: Despite recent therapeutic advances, combating Cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both Cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 Infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress Cancer and COVID-19.

Results: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and Autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances Apoptosis, sensitizes colorectal Cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon Cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast Cancer xenograft model. Furthermore, OLN blocks Infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated Cancer cell apoptotic onset and suppression of virus release.

Conclusion: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat Cancer and COVID-19.

Keywords

Anti-cancer therapy; Anti-viral therapy; Breast cancer; Cardiac glycosides; Colon cancer; ER stress; GRP78; Oleandrin; SARS-CoV-2.

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