Abstract B62: Role of classical protein kinase C (PKC) in intestinal cancer

Abstract PKCs represent a family of serine/threonine kinases consisting of a least 10 isoforms, divided into three subclasses based on their Ca2+ and DAG dependency. The classical PKC (cPKC) isoforms alpha, beta-I, beta-II, and gamma are calcium and diacylglycerol (DAG) dependent whereas novel PKCs (delta, epsilon, eta, and theta) are calcium independent. In contrast the atypical PKC zeta and lambda/iota do neither need calcium ions nor DAG for their activation. All PKCs are thought to be involved in cell growth and differentiation. In particular, studies focusing on expression profiles of PKCs during tumor formation and progression imply a functional link. For example, have we been able to show that PKC-alpha and -beta are differently regulated in the APCMin mouse model, which represents a well-established model for intestinal cancer. Based on these data, we further have identified PKC-alpha as to act like a tumor suppressor in this context. Given the fact that PKCs are activated by PMA/TPA and therefore defined as tumor promotors, this was a very surprising observation. Material and Methods: This project makes use of mouse intestinal epithelial cell lines that we established from various genetic backgrounds. Using standard Western blot protocols, we first analyzed the abundance and activation status of different signal cascades upon epidermal growth factor (EGF) stimulation. Results: Earlier studies by us (Oster and Leitges, 2006) have indentified an alteration of the EGF receptor signaling in the APCMin model due to PKC-alpha deficiency. To understand the underlying mechanism, we analyzed EGF receptor signaling in mouse intestinal epithelial cell lines. Thus far it became obvious that PKC-alpha deficiency causes a prolonged Erk1/2 and Akt activity whereas JNK activation was only detectable in the alpha deficiency. Conclusion: In sum, we have shown that EGF receptor signaling capacity is functionally linked to PKC-alpha activity. Literature: Oster H, Leitges M. Protein kinase C alpha but not PKC zeta suppresses intestinal tumor formation in APCmin mice. Cancer Res. 2006;66:6955–6963. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B62.