IQGAP1 plays an important role in the cell proliferation of multiple myeloma via the MAP kinase (ERK) pathway

Abstract

The present study was designed to explore the role of IQ motif-containing GTPase activating protein 1 (IQGAP1) in the cell proliferation of multiple myeloma (MM) via the MAP kinase (ERK) pathway. Reverse transcription‑polymerase chain reaction (RT-PCR) and western blot analysis were carried out to evaluate the expression of IQGAP1 in RPMI8226, U266 and KM3 cell lines and in primary MM cells from 4 MM patients. shRNA-expressing plasmids were used in RPMI8226 cells to knock down IQGAP1 and an MTT assay was used to examine the proliferative activity of the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells in subgroups stimulated with VEGF/IL-6 or without. Western blot analyses were then performed to examine the protein levels of p-ERK1/2, ERK1/2, AKT, p-AKT, STAT3, p-STAT3 in the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells. Co-immunoprecipitation was used to verify the interaction between the IQGAP1 scaffold and the MAP ERK kinase. We found that IQGAP1 was overexpressed in the human myeloma cell lines and in the patient MM cells. The proliferation rate in the RPMI8226 cells was decreased when IQGAP1 was knocked down with shRNA. IQGAP1 was found to affect RPMI8226 cell proliferation by regulation of the MAP kinase (ERK1/2) pathway; IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.

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

“…In this study we examine a novel approach to disrupt the interaction between IQGAP1 and MAPK and determine the biologic effects of RAS/MAPK signaling on MM self-renewal. We found that IQGAP1 knockdown inhibited RAS/MAPK signaling as has been previously been shown (29, 30). Moreover, targeting IQGAP1 with a small peptide mimetic that binds to ERK also effectively blocked MAPK signaling, decreased clonogenic growth and self-renewal in vitro , and inhibited MM tumor initiating cell frequency of NCI-H929 cells engrafted in immunodeficient mice.…”

“…Previous studies have shown that IQGAP1 expression is required for RAS/MAPK signaling and cell growth both in solid tumor models and in MM (24, 29, 30). However, it is not known whether IQGAP1 loss-of-function mimics the cell cycle arrest observed with direct MAPK pathway inhibition in MM (19, 21, 39).…”

Caffeic acid improves cell viability and protects against DNA damage: involvement of reactive oxygen species and extracellular signal-regulated kinase

“…The ERK pathway typically transduces growth factor signals that lead to cell differentiation or proliferation (7); however, the association of ERK with CaA-induced improvement of cell viability and subsequent protection against DNA damage is unclear. We exposed L-02 cells to 10 μM CaA for 0, 3, 6, 12, or 24 h, and found that with increased time of CaA exposure, there was enhanced expression of p-ERK, a biomarker for the activation of ERK signaling (Figure 4A and B).…”

“…MAPKs including ERK, p38 MAPK, and JNK are key components of signaling pathways that control cell differentiation and growth (9,30,31). There is evidence that MAPKs can be phosphorylated and activated in response to oxidant-induced alterations of the redox state (7). After activation, each MAPK phosphorylates a distinct spectrum of substrates including key regulatory enzymes, cytoskeletal proteins, regulators of apoptosis, nuclear receptors, and many transcription factors that bind to specific DNA sequences and induce transcriptional activation and DNA synthesis, with cellular recruitment to the S-phase (9,30,32).…”

“…The MAPK pathways transduce signals that lead to diverse cellular responses such as cell growth, differentiation, proliferation, and apoptosis (7-9). Each of the three major MAPK pathways consists of three-tiered cascades that induce a pathway comprised of phosphorylating proteins that mediate transduction pathways activated by a variety of extracellular signals and regulate the expression of specific genes (10,11).…”