**11.2. Immunogenecity of cancer cell death**

86 Apoptosis and Medicine

**Figure 11.** Akt signalling pathway

**Akt.** Classically, the phosphoinositide-3-kinase (PI3K)-Akt-mTOR pathway is described as a key signal transduction cascade that integrates signals from growth factors and nutrients to regulate cell growth and proliferation [122]. Following growth factor binding to cell surface receptors, PI3K is activated and phosphorylates phosphatidylinositol-4,5-biphosphate (PIP2) to generate the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). This process can be inhibited by the tumour suppressor protein phosphatase and tensin homolog (PTEN), which dephosphorylates PIP3 and terminates PI3K signalling. Then, the accumulated PIP3 recruits PDK1 and Akt through their Pleckstrin homology domains, and Akt is activated [123]. Akt recognizes and phosphorylates a consensus sequence that is present in many proteins. These substrates control key cellular processes such as apoptosis, cell cycle progression, transcription, and translation, all of which are critical events in cancer [124]. The Akt signal transduction pathway is probably the best survival pathway characterized. Moreover, Akt is constitutively activated in several malignant tumours, such as prostate, breast, ovary, lung and liver carcinomas [125]. Akt suppresses apoptosis through different mechanisms, including phosphorylation of forkhead transcription factors, which regulate proapoptotic proteins such as Bim and Fas ligand. The phosphorylated forkhead proteins are trapped in the cytosol and cannot enter the nucleus. Akt also phosphorylates and inactivates several proapoptotic proteins like Bad and caspase-9. Importantly, it activates IKK inducing the transcription factor NF-κB, leading to transcription of several antiapoptotic proteins such as Bcl-xL, and XIAP [96,126]. Akt also It is becoming more evident that the immune response facilitates the effects of chemotherapy. Physiological death avoids autoimmunity. However cancer cell death triggered by radiotherapy or some chemotherapeutic agents such as anthracyclines can be immunogenic [128]. Immunogenic death involves changes in the composition of the cell membrane and the release of molecules called Damage Associated Molecular Patterns or alarmins. In particular, calreticulin has been shown to be crucial for immunogenic cancer cell death [129]. The immune system determines the long-term success of antitumor therapies. It seems that mitochondrial events as well as the ER response in conjunction with autophagy can establish whether cancer cells die in response to chemotherapy [130]. It has been found that calreticulin is the dominant pro-phagocytic signal on several cancers including neuroblastoma, non Hodgkin's lymphoma and bladder cancer. However, calreticulin is counterbalanced by the "don´t eat me" signal CD47, which prevents cancer cell phagocytosis and is also highly expressed in these tumours [131]. Moreover, since CD47 is expressed on the surface of all human cancer cells but not in normal cells, blocking CD47 function with antibodies is emerging as a novel potential cancer strategy [132].
