Akt regulation and lung cancer: a novel role and mechanism of action for the tumor suppressor Par-4.

The balance between oncogenic and tumor-suppressive signals is central to the control of tumor initiation and progression. Our laboratory identified Par-4, a gene previously discovered in a screen for genes upregulated in cells undergoing apoptosis, as a critical negative regulator of the aPKCs. Par-4 inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumor development, and low-frequency carcinogenesis. We recently showed that the loss of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, and that, whereas Par-4 is highly expressed in normal lung, it is reduced in a significant proportion of human non-small cell lung carcinomas, strongly suggesting that Par-4 is a relevant tumor suppressor in lung cancer. From a mechanistic point of view, these results unveiled an unexpected and important role of Par-4 as a negative regulator of Akt. We have demonstrated in cell culture, in vivo, and in biochemical experiments that Akt regulation by Par-4 is mediated by PKC zeta, establishing a new paradigm for Akt regulation and demonstrating in vivo that PKC zeta is a physiologically relevant partner of Par-4.