PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis
Menée sur des cellules basales murines et in vivo, cette étude met en évidence le rôle de la voie de signalisation PI3K/AKT/mTOR dans la chimioprévention des carcinomes basocellulaires par les rétinoïdes
Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via RARγ-mediated regulation of tumor cell transcription. Since topical retinoids can cause adverse cutaneous effects and since tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's anti-tumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the PI3K/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anti-cancer effects.