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- Title
Targeting N-myristoylation for therapy of B-cell lymphomas.
- Authors
Beauchamp, Erwan; Yap, Megan C.; Iyer, Aishwarya; Perinpanayagam, Maneka A.; Gamma, Jay M.; Vincent, Krista M.; Lakshmanan, Manikandan; Raju, Anandhkumar; Tergaonkar, Vinay; Tan, Soo Yong; Lim, Soon Thye; Dong, Wei-Feng; Postovit, Lynne M.; Read, Kevin D.; Gray, David W.; Wyatt, Paul G.; Mackey, John R.; Berthiaume, Luc G.
- Abstract
Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma. N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.
- Subjects
CANCER cells; MEMBRANE proteins; RITUXIMAB; MYRISTOYLATION; CELL death; CELL lines; CD19 antigen
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-18998-1