The chromatin protein and sensor of stress p8 mediates pancreatic cell survival and PanIN development via a RelB/IER3-dependent pathway.

TEWFIK HAMIDI; HANA ALGÜL; CARLA E CANO; MARIA JOSÉ SANDI; MARIA INÉS MOLEJON; MARC RIEMANN; EZEQUIEL L CALVO; GWEN LOMBERK; JEAN-CHARLES DAGORN; FALK WEIH; RAUL URRUTIA; ROLAND M SCHMID; JUAN L IOVANNA

Encuentro; 43rd Meeting of the European Pancreatic Club (EPC); 2011

PDAC develops within a hypovascularized microenvironment that imposes a stringent selection of cancer cells that are resistant to oxygen and nutrient deprivation. However, the molecular mechanism/s by which PDAC cells become resistant to these stresses remain largely unknown. Among the potentially implicated stress proteins, p8 is an interesting candidate because its implication in apoptosis inhibition and its systematic over-expression in PDAC. In this study, we showed that p8 expression is activated in vitro in response to starvation and that its expression is necessary for cell survival in nutrient deprived conditions. p8 expression protects from starvation-induced cell death by inhibiting apoptosis through an alternative RelB ->IER3-dependent mechanism, but not to the classical RelA-based NF-kB pathway. In vivo, we observed that p8 is mandatory for the development of PanIN lesions in KrasG12D mice, and that these lesions express both RelB and IER3 proteins. In addition, KrasG12D;Relbpanc mice, which are pancreas specific RelB-ablated, showed an important delay in the development of PanINs, and these lesions do not express IER3. Hence, efficient PanINs formation appears to be dependent on the expression of p8, RelB and IER3. Altogether, our results reveal an original intracellular pathway named p8 -> RelB -> IER3, which is initiated in response to nutrient deprivation and that seems to be involved in development of PDAC.