Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim

Abstract

Notch signaling is a highly conserved pathway important for normal embryonic development and as well as cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the EGFR pathway was also inhibited, suggesting significant crosstalk between these two pathways. How Notch3 and EGFR/MAPK pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using γ-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were enhanced compared to either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR/ras/MAPK signaling. Thus, our data support the hypothesis that Notch3 not only plays a crucial role in lung cancer through regulating apoptosis but also cooperates with the EGFR/MAPK pathway in modulating Bim.

MUC5AC Expression through Bidirectional Communication of Notch and Epidermal Growth Factor Receptor Pathways

“…In lung cancer cells, expression of Notch3 is positively correlated with EGFR expression, and dominant-active Notch3 activates ERK phosphorylation, whereas dominant-negative Notch3 inhibits ERK phosphorylation. Furthermore, Notch3 siRNA or GSI inhibits ERK phosphorylation, and the effect of Notch signaling is impeded by both ERK and EGFR inhibitors (47)(48)(49). In addition, Notch1 upregulates EGFR expression through p53 (50).…”

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

“…Several investigators have proposed the activation of growth factor receptor pathways, such as PDGF or EGF, as hallmarks of podocyte-activation and crescent formation during GN. [15][16][17] Because Notch3 was found to induce activation of these growth factor receptors in lung cancer and in smooth muscle cells, 18,19 it is possible that a similar interaction occurs in the activated podocytes. In agreement with this hypothesis, Notch3 antisense delivery inhibited the NTS-induced activation of these pathways in our study ( Figure 5).…”

Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer

“…In the GSI group, 200 µg/kg GSIXX was administered i.p. on days 2, 3, 4 and 9, 10, 11, as previously described [11,18]. In the YC-1 group, 15 µg/g YC-1 was administered by i.p.…”

“…Tumor volume (TV) was determined using the formula: TV = (length) × (width) × (height)/2 [20]. Tumor growth rate (%TV) on day X was calculated as: (TV on day X/TV on day 1) ×100, as previously described [18]. Some tumors were resected on day 15 for Western blotting analysis and immunohistochemistry.…”