IQGAP1 Scaffold-MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal.

Abstract

Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1. Mol Cancer Ther; 15(11); 2733-9. ©2016 AACR.

• Authors: Christian B Gocke, Ross McMillan, Qiuju Wang, Asma Begum, Vesselin R Penchev, Syed A Ali, Ivan Borrello, Carol Ann Huff, William Matsui
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 11 Pg. 2733-2739 (11 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27573425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• IQ motif containing GTPase activating protein 1
• Peptides
• ras GTPase-Activating Proteins
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Biological Mimicry
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Self Renewal (drug effects, genetics)
• Clonal Evolution (drug effects, genetics)
• Disease Models, Animal
• Female
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Multiple Myeloma (drug therapy, metabolism, mortality, pathology)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Peptides (chemistry, pharmacology)
• Protein Interaction Domains and Motifs
• Xenograft Model Antitumor Assays
• ras GTPase-Activating Proteins (antagonists & inhibitors, chemistry, metabolism)