Biological and biochemical consequences of PTEN inactivation: Drug resistance and the role of JNK in PIP3-driven tumorigenesis.

摘要

The tumor suppressor PTEN is one of the most commonly mutated genes in human malignancies. Homozygous deletion of PTEN in mice results in embryonic lethality, but heterozygous animals develop multiple tumors. The tumor suppressive function of PTEN has been linked to its lipid phosphatase activity which antagonizes PI3K function. Until now, most of the biological consequences of PTEN loss have been attributed to the activation of the PI3K downstream target AKT, a serine/threonine kinase which regulates apoptosis, cell cycle progression and glucose metabolism. However, activation of AKT alone is not sufficient to induce transformation, suggesting the existence of parallel pathways downstream of PI3K which can complement AKT. We find that cells with a targeted deletion of PTEN show increased JUN N-terminal kinase (JNK) activity and that this increase is independent of AKT activation. Furthermore, PTEN knockout mouse embryonic fibroblasts (KO MEF) show increased sensitivity to both genetic and pharmacological inhibition of JNK compared to wild type MEF demonstrating that the JNK pathway is critical for growth in PTEN-null cells. Interestingly, neither activated AKT nor activated JNK alone are able to induce transformation in mouse fibroblasts, but the combination results in colony formation in soft agar and tumor growth in mice. These results place JNK as a critical component of the PTEN/PI3K pathway and make it a very attractive therapeutic target for tumors with PTEN mutations.;Finally, we found that another consequence of PTEN inactivation is the development of resistance against the pro-apoptotic effects of various EGFR inhibitors in both experimental cell lines and glioblastoma patients. However, AKT activation is not sufficient to confer resistance suggesting the existence of PTEN-dependent AKT-independent modulators of response.