Abl interconnects oncogenic Met and p53 core pathways in cancer cells

Abstract

The simplicity of BCR-ABL 'oncogene addiction' characterizing leukemia contrasts with the complexity of solid tumors where multiple 'core pathways', including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser(392) and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature.Cell Death and Differentiation advance online publication, 1 April 2011; doi:10.1038/cdd.2011.23

Activation of Abl Family Kinases in Solid Tumors

“…119 Sustained activation of c-Abl, downstream of constitutively active c-Met, promoted survival during nutrient deprivation, anchorage-independent growth, and tumorigenesis in gastric and/or liver cancer cells. 89 Interestingly, activated c-Abl induced p38 phosphorylation and subsequent phosphorylation of p53 (S393), leading to increased p53 transcriptional activity and upregulation of p53 targets (Mdm2) (Fig. 1).…”

“…1). 89 In liver cancer cells, c-Abl is activated downstream of overexpressed claudin-1, a tight junction protein whose increased expression is associated with an advanced, aggressive phenotype. 90,91 High-level c-Abl expression also was observed in primary anaplastic M Monographs thyroid carcinomas but not in follicular or papillary carcinomas or in normal thyroid tissue, and c-Abl expression correlated with mutant p53 expression.…”

ATM kinase sustains HER2 tumorigenicity in breast cancer

“…Viability was assessed 72 h after treatment, with the Cell Titer GloLuminescent Assay (Promega). Anchorage-independent growth assays were performed as described 48 . Data on biological assays are representative of three independent experiments performed in triplicate.…”

“…At day 0, SCID mice were fully anesthetized and 17-h estradiol pellets were subcutaneously injected. The day after, 5 Â 10 6 exponentially growing MCF7-HER2 cells were mixed 1:1 with Matrigel (BD Biosciences, San Jose, CA, USA) and injected subcutaneously as previously described 48 . Tumour development was followed twice a week by caliper measurements along two orthogonal axes: length (L) and width (W).…”

Le récepteur Met fête ses 30 ans

“…La voie PI3K, via l'activation d'Akt (protéine kinase B), joue aussi un rôle central dans la survie cellulaire induite par Met [18], tout comme la régulation de p53 par Abl et p38 [19]. Au cours des années 2000, différents mécanismes de régulation négative du récepteur Met ont été mis en évidence.…”