Role Of The Tumor Microenvironment In Mediating Drug Resistance And It's Multi-reverse

The emergence of clinical drug resistance continues to be an obstacle for the successful treatment of cancer. Extracellular matrix (ECM) may provide a sanctuary for subpopulations of tumors cells that affords a survival advantage following initial drug exposure and may facilitate the acquisition of acquired drug resistance. In this study we have used adhesion-mediated drug resistance model (CAM-DR) as an in vitro model. We delineated a pathway that involves fibronectin/PI-3K/Akt in mediating drug resistance in human ovarian and breast cancer cells. We found that stable expression of Akt2 in malignant human breast and ovarian cells. Transfection of AAkt2 (Full-length AKT2 cDNA) in breast and ovarian cells leads to increased Akt phosphorylation and activity and is associated with an increased resistance of the cells to chemotherapeutic agents docetaxel. Fibronectin adhesion increases Akt activation in highly metastatic cancer cells but not in nonmetastatic cancer cells. Fibronectin/ PI 3-Kinase/Akt induced survival signaling protects A2780 and MDAMB231 Cells from docetaxel induced Apoptosis. We further demonstrated that A2780 cells and MDAMB231 cells cotransfected with two shRNA vector targeting the same Akt2 mRNA showed a significant increased sensitivity to docetaxel. Docetaxel induced apoptosis in ovarian and breast cancer cells is associated with decreased levels of survivin, and appropriate cell-fibronectin interaction in turn block this event, and it was associated with activation of the PI 3-Kinase/Akt pathway. Our results suggest that activation of Akt2 by FN/PI-3K plays an important role in conferring chemoresistance on ovarian and breast cancer cells and Akt2 protects against docetaxel induced apoptosis through regulating survivin protein expression. An association between Akt and ASK1 was detected in cells by coimmuno -precipitation. Phosphorylation by Akt inhibited ASK1-mediated P38 activities in intact cells.Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 These results provide the first direct link between Akt and the family of stress-activated kinases. In conclusion, our data indicate that Akt plays an important role in protecting human ovarian and breast cancer cells against chemotherapy through fibronectin adhesion. AKT2 inhibits docetaxel-inducedp38 activation through phosphorylation of ASK1 and thus, plays an important role in chemoresistance. Further, regulation of the ASK1/ /p38/ pathway by AKT2 provides a new mechanism contributing to its antiapoptotic–effects.