Basic Study

DNA damage pathway and inhibition of AKT-mTOR pathway in cancer cells

Microwave therapy induces apoptosis via activation of DNA damage pathway and inhibition of AKT-mTOR pathway. As shown in Figure below, we examined the influence on heat shock proteins such as HSP70 or 90, in H322 cells treated with microwave irradiation, which increased the expression of HSP70 but did not show significant influence to HSP90. It has been reported that expression of HSP70 in response to microwave treatment induces antitumor immunity, and HSP90 has been specifically involved in the maintenance of the correct conformation of several intracellular proteins and much of them are kinases involved in the control of cell proliferation and survival such as Raf-a and AKT. Double-stranded DNA breaks (DSBs) induced by γ-irradiation or various chemotherapeutic agents activates the DNA damage pathway through phosphorylation of several molecules, including Histone H2AX, Chk2, and Chk1, and such checkpoint mechanisms allow the cell time to repair the DNA damage before cell cycle progression is resumed, or, if the damage is too extensive, they trigger apoptosis or cellular senescence. AKT-mTOR pathway, which is activated in many types of cancer, is important in apoptosis, since phosphorylation of AKT inactivates the proapoptotic factors and activates the mTOR which phosphorylates the downstream molecules leading to apoptosis. It was also recently reported that DSBs are involved in heat-induced cell killing for foci formation ofγ-H2AX (phosphorylation of histone H2AX at serine 139), and microwave electromagnetic field at 1.95 MHz inhibits the expression of AKT.γ-H2AX and phospho-Chk2 increased and total AKT, phospho-AKT, and phospho-mTOR decreased in cells irradiated with the Microwave hyperthermia in temperature dependent manner compared to control cells, on the other hand, total Chk2 and PTEN is at the same level in cells of all treatments, suggesting that the Microwave hyperthermia remarkably activated the DNA damage checkpoint pathway and inactivated the AKT-mTOR pathway. (Results from experiments conducted by Dr. Motomura Tadashi, Associate Professor, Baylor College of Medicine, United States).