which in turn is a potent agent of DNA damage causing DNA fragmentati

rapamycin facilitates Bad translocation from mitochondria into the cytosol, and promotes Bad interaction with 14 3 3 and its dissociation from Bcl XL. The overall outcome of this series of effects in the inability of Bad to overcome the antiapoptotic function of Bcl XL in the mitochondria. Additionally, treatment of lung cancer cells with rapamycin promotes Bad ubiquitination and degradation, Cabozantinib leading to a reduced half life and ultimately a loss of function. Because Bad is a potent BH3 only proapoptotic protein that is ubiquitously expressed in both SCLC and NSCLC cells, blocking rapamycin induced Bad phosphorylation may represent a novel therapeutic strategy for improving the anti tumor efficacy of rapamycin. Although rapamycin can induce Bad phosphorylation at two sites, PD98059 blocks Bad phosphorylation only at the S112 site while depletion of Akt blocks Bad phosphorylation only at the S136 site in either lung cancer cells or in lung tumor tissues. These findings provide strong evidence Retroperitoneal lymph node dissection that rapamycin induced S112 site phosphorylation occurs through the MEK/ERK1/2 signaling pathway while rapamycininduced S136 site phosphorylation occurs through the Akt pathway. Abrogation of rapamycin stimulated phosphorylation of Bad at S112 and S136 led to increased growth inhibition of lung cancer cells in vitro and synergistic enhancement of rapamycin activity against lung cancer tumor xenografts in vivo. In summary, our studies identify a novel rapamycin survival signal transduction pathway that depends on phosphorylation of Bad at S112 and S136 but not S155 through activation of MAPKs ERK1/2 and Akt. Rapamycin induced double site phosphorylation in translocation of Bad from the mitochondria, sequestration in the cytosol where it interacts with 14 3 3, dissociation from Bcl XL in mitochondria AG-1478 and reduced stability via ubiquitination, which leads to loss of the apoptotic function of Bad and rapamycin resistance. Our findings have established Bad as a new signaling target of rapamycin in human lung cancer cells. Therefore, activation of Bad by reducing or blocking its phosphorylation may represent a new therapeutic strategy to overcome resistance to mTOR inhibition in patients with lung cancer. Dysregulated ?? catenin signaling is intricately involved in renal cell carcinoma carcinogenesis and progression. Determining potential ?? catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for ?? catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI resistant RCC cell lines.