The Phosphoinositide 3-Kinase/Akt1/Par-4 Axis: A Cancer-Selective Therapeutic Target

Abstract

Activation of the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway in many cancers makes it an appealing target for therapeutic development. However, because this pathway also has an important role in the survival of normal cells, tactics to achieve cancer selectivity may prove important. We recently showed that the cancer-selective proapoptotic protein Par-4 is a key target for inactivation by PI3K/Akt signaling. Additionally, we found that Par-4 participates in mediating apoptosis by PTEN, the tumor suppressor responsible for blocking PI3K/Akt signaling. As a central player in cancer cell survival, Par-4 may provide a useful focus for the development of cancer-selective therapeutics. (Cancer Res 2006; 66(6): 2889-92)

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

“…Mitogen-activated protein kinase signaling also does not seem to play a central role. Instead and in line with several reports (28,38), activation of the PI3K/Akt pathway obviously is decisive. CD44v cross-linking promotes Akt phosphorylation in ASML wt cells; accordingly, ASMLCD44v kd cells display impaired PI3K/Akt signaling.…”

Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis

“…It plays a central role in signaling by the PI3-K pathway by regulating many biological processes, such as proliferation, apoptosis and cell growth (Cantley et al, 2002). In addition, the activated PI3K-Akt pathway provides major survival signals to lymphoma cells and many other cancer cells (Goswami et al, 2006;Toker and Yoeli-Lerner, 2006). Akt controls a variety of mechanisms that inhibit apoptosis and prolong cell survival, exerting a positive effect on NF-kB functions (Ozes et al, 1999;Osaki et al, 2004).…”

Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts

“…AKT is a crucial survival kinase, and interfering with AKT expression is an attractive strategy to control tumour progression (Goswami et al, 2006). Interestingly, the present data show that tumour regrowth was accompanied by marked changes in tumour expression of PTEN and phospho-AKT.…”