Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras

Abstract

Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and KRas). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB-and Ras-driven cancers. Cancer Res; 71(6); 2140-51. Ó2011 AACR.

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

“…This is compatible with the fact that the gene network controlling the maintenance of aggressive phenotype appears mainly under positive control by miRNAs (Polyak and Weinberg, 2009;Inui et al, 2010;Martello et al, 2010), whereas the effects on proliferation might not reveal immediate phenotypic consequences in virtue of the "balancing effect" between miRNAs favoring and opposing the same process (Ventura and Jacks, 2009). Moreover, our data are in agreement with previously published data demonstrating that NCL also exerts an miRNA-independent role in cancer cell proliferation and tumorigenicity (Shi et al, 2007;Reyes-Reyes and Akiyama, 2008;El Khoury et al, 2010;Destouches et al, 2011;Farin et al, 2011;Wu et al, 2012). This is the first study of the functional role of NCL in miRNA regulation with clear clinical implications.…”

“…These findings support the idea that NCL might be considered a cancer cell-specific receptor that is able to mediate tumor-selective uptake of specific molecules. The importance of NCL in cancer biology was recently highlighted by studies showing that NCL plays a critical role in tumorigenesis and angiogenesis (Shi et al, 2007;Reyes-Reyes and Akiyama, 2008;El Khoury et al, 2010;Destouches et al, 2011;Farin et al, 2011;Wu et al, 2012). Furthermore, the ability of this protein to bind specific RNA and G-rich DNA elements with high affinity (Brooks and Hurley, 2010;Abdelmohsen et al, 2011;Sun et al, 2011) makes it targetable by the first G-rich aptamer (AS1411) that has reached phase II clinical trials for cancer therapy (Teng et al, 2007;Soundararajan et al, 2008;Bates et al, 2009a;Keefe et al, 2010).…”

Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma

“…In our earlier studies, we have identified a functional crosstalk between Ras, nucleolin and ErbB1 [22, 24]. In the present study we examined the effect of two drugs, directed towards Ras and nucleolin proteins, as a tool to disrupt the synergism between these three oncogenes as a potential treatment for glioblastoma.…”

“…This interaction leads to ErbB1/EGFR receptor activation as well as to colony growth in soft agar [20]. In addition, recently we identified a crosstalk between nucleolin, ErbB1 and Ras proteins [22]. More recently, we have demonstrated that treatment of colon and prostate cancer cells with FTS and GroA (AS1411) inhibited cell growth and anchorage independent growth [24].…”

A DDX31/Mutant–p53/EGFR Axis Promotes Multistep Progression of Muscle-Invasive Bladder Cancer

“…4A and B). Furthermore, accumulating evidence has shown that cytoplasmic NCL interacts with erbB receptors, and especially enhances epidermal growth factor receptors (EGFRs), thereby enhancing EGFR dimerization and activation and promoting EGF ligand-independent cell growth (25,26). Therefore, we focused on EGFR as a partner of the DDX31-NCL complex and performed immunoprecipitation with an anti-EGFR antibody, followed by Western blot with NCL and DDX31 antibodies.…”