Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Abstract

The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ

“…Notably, the pro-apoptotic function of PKCδ has been linked to the downstream activation of p53, and its transcriptional targets (p21 and PUMA), suggesting a mechanism through which suppression of PKCδ may reduce the apoptotic response (26,27). A report by Barckhausen et al also demonstrates that inhibition of apoptosis can promote DNA repair (28), consistent with a reported role for PKCδ in regulation of DNA repair (23). …”

“…Attempts to protect salivary gland function have focused on use of free radical scavengers such as amifostine (4) to reduce cell injury, and growth factors such as FGR, IGF and KGF to stimulate gland regeneration (19–22). Our approach to reducing IR toxicity to the salivary gland is based on inhibiting the activation of PKCδ, a pro-apoptotic protein kinase required for DNA damage induced apoptosis in vitro and in vivo (23). …”

PKCδ inhibition as a novel medical countermeasure for radiation‐induced vascular damage

“…Previously, the serine/threonine kinase PKCd has been identified as a critical regulator of the inflammatory response (19)(20)(21)(22)(23). Moreover, PKCd 2/2 -deficient mice were protected from radiation-induced damage to the salivary gland and thymus (24,25). Thus, we hypothesize that PKCd is activated in response to radiation, and PKCd inhibition modulates radiation-induced endothelial permeability and protects tissue against neutrophil-mediated damage.…”

Clinicopathological characteristics of KIT and protein kinase C‐δ expression in adenoid cystic carcinoma: comparison with chromophobe renal cell carcinoma and gastrointestinal stromal tumour

“…In addition, PKC‐δ inhibits cell cycle progression and up‐regulates apoptosis in prostate cancer . However, in‐vitro studies support the role of PKC‐δ as a tumour promoter . Therefore, further studies are required to elucidate the role of PKC‐δ as a tumour suppressor.…”