Role of protein kinase D signaling in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal survival rates. Its intransigence to conventional therapy renders PDAC an aggressive disease with early metastatic potential. Thus, novel targets for PDAC therapy are urgently needed. Multiple signal transduction pathways are implicated in progression of PDAC. These pathways stimulate production of intracellular messengers in their target cells to modify their behavior, including the lipid-derived diacylglycerol (DAG). One of the prominent intracellular targets of DAG is the protein kinase C (PKC) family. However, the mechanisms by which PKC-mediated signals are decoded by the cell remain incompletely understood. Protein kinase D1 (PKD or PKD1, initially called atypical PKCµ), is the founding member of a novel protein kinase family that includes two additional protein kinases that share extensive overall homology with PKD, termed PKD2, and PKD3. The PKD family occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes. We and others have shown that PKD-mediated signaling pathways promote mitogenesis and angiogenesis in PDAC. Our recent observations demonstrate that PKD also potentiates chemoresistance and invasive potential of PDAC cells. This review will briefly highlight diverse biological roles of PKD family in multiple neoplasias including PDAC. Further, this review will underscore our latest advancement with the development of a potent PKD family inhibitor and its effect both in vitro and in vivo in PDAC.

Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

“…PKDs are involved in the regulation of important cellular features such as proliferation (10,11,13,(35)(36)(37), motility, and invasiveness (2-5) of different tumor types. However, specific and detailed functions for distinct PKD isoforms have not been addressed so far.…”

“…However, it is unclear whether these functions are regulated by all PKD isoforms in a similar fashion and via the same PKD targets or substrates. Therefore, we investigated how PKD1 and PKD2, two PKD isoforms that mediate vital functions in pancreatic tumor growth and angiogenesis, are involved in the regulation of pancreatic cancer cell growth (12)(13)(14). We initiated a bioinformatics screening approach using Scansite (15) to identify putative PKD phosphorylation consensus motifs in potentially relevant PKD substrates and identified (in accordance with Du et al (16)) Snail1 as a putative PKD substrate.…”

Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation

“…It has been reported that PKD1 could promote pancreatic cancer development (38). In contrast, some studies suggested PKD1 might have anticancer function in androgen-independent prostate cancer (39), breast cancer (34), and gastric cancer (40).…”

Opposing Growth Regulatory Roles of Protein Kinase D Isoforms in Human Keratinocytes

“…Aberrant PKD activity and expression have been shown in a number of tumors including breast, skin, prostate, and pancreatic cancers (3)(4)(5). Most of our current understanding of PKD function, however, is based on characterization of PKD1, the founding member of this family; less is known about the function of other two isoforms (1,6,7).…”