Th2 cytokines induce chemotherapy resistance in epithelial tumors via PI3K/AKT pathway

Abstract

Several studies designate apoptosis as the predominant mechanism by which cancer cells die in response to chemotherapeutic drugs. Moreover, it was suggested that anti-apoptotic molecules activation play a pivotal role in the chemotherapeutic drugs resistance. We have recently demonstrated that the presence of Th2 cytokines in thyroid cancer microenvironment increase FLIP, Bcl-2 and Bcl-xl expression levels and protect cancer cells from chemotherapeutic drugs induced apoptosis. Particularly, in this study we demonstrate that IL-4 and IL-10 promote proliferation and chemotherapy resistance activating the PI3K/AKT signal pathway. Therefore, we extensively studied cell survival-related substrates and their modulation by Th2 cytokines in epithelial tumors. These substrates include members of intrinsic cell death machinery such as BAD and caspase 9, and forkhead family members and the transcriptional factor NF-kB, which seems to exert a key role in promoting anti-apoptotic genes expression. These findings elucidate a key molecular mechanism by which tumor cells escape conventional chemotherapy.