Regulation of Cell Death by Protein Kinase C: Implications for Tissue Damage and Tumorigenesis
Apoptosis, or regulated cell death, is critical for vertebrate development and the clearance of damaged or genetically altered cells. Apoptosis is also induced by a variety of exogenous agents including irradiation, chemotherapeutic drugs and cell toxins.
The importance of these pathways is illustrated by the fact that genetic disruption of apoptosis is commonly seen in cancer. My laboratory is interested in how specific members of the protein kinase C (PKC) family of lipid-regulated serine/threonine
protein kinases function to modulate apoptosis, and how this knowledge can be applied to treat cancer, or in some cases to protect against damage to “normal” tissues caused by cancer therapies. Major areas of emphasis in the lab include:
The mechanism of regulation of apoptosis by PKCδ Our studies demonstrate that PKCδ is an early and essential regulator of apoptosis in epithelial cells, and that disruption of the PKCδ gene in mice results in resistance to irradiation-induced apoptosis
in vivo. To explore the mechanism underlying PKCδ regulation of apoptosis, we have used cultured epithelial cells or genetically modified mice that have specific defects in protein kinase C directed signal transduction. Based on these studies we hypothesize
that PKCδ functions in the nucleus to integrate death signals. Current questions include:
- What is the role of PKCδ in regulation of DNA double stranded break repair?
- Can we identify phosphorylation targets of PKCδ and DNA-damage induced proteins that associate with PKCδ in apoptotic cells?
Inhibition of PKCδ protects against irradiation-induced damage to oral tissues:
In patients undergoing irradiation therapy for head and neck cancer, injury to non-tumor tissues can result in debilitating, and often permanent, side effects. Our understanding of how PKCδ is activated by DNA damage lead us to predict that tyrosine kinase
inhibitors could be used to block activation of PKCδ for radioprotection of the salivary gland. Our studies show robust protection of salivary gland function in mice treated with irradiation and tyrosine kinase inhibitors, suggesting that TKIs may be
useful clinically to protect non-tumor tissue in HNC patients undergoing radiotherapy, without negatively impacting cancer treatment.
- Together with a team that includes radiation and molecular oncologists, we are designing a clinical trial for radioprotection of non-tumor tissues in patients undergoing irradiation for head and neck cancer.
The role of PKCδ in cancer:
As disruption of apoptosis contributes to cancer progression, we have initiated studies to understand the role of protein kinase C in these processes. Surprisingly, our studies indicate that PKCδ can function as a tumor promoter in some types breast and
lung cancer, through a mechanism that is independent of apoptosis. This exciting data suggests that PKCδ can regulate signal transduction pathways that promote cell transformation and cancer cell growth. Current questions include:
- How does PKCδ regulate pro-proliferative signals in cancer cells?
- Does PKCδ regulate the interaction of cancer cells with the extracellular environment?
- Is PKCδ activation altered in human tumors?