Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer

Heike Döppler,Peter Storz

doi:10.3389/fonc.2017.00041

Abstract

Due to alterations in their metabolic activity and decreased mitochondrial efficiency, cancer cells often show increased generation of reactive oxygen species (ROS), but at the same time, to avoid cytotoxic signaling and to facilitate tumorigenic signaling, have mechanism in place that keep ROS in check. This requires signaling molecules that convey increases in oxidative stress to signal to the nucleus to upregulate antioxidant genes. Protein kinase D1 (PKD1), the serine/threonine kinase, is one of these ROS sensors. In this mini-review, we highlight the mechanisms of how PKD1 is activated in response to oxidative stress, so far known downstream effectors, as well as the importance of PKD1-initiated signaling for development and progression of pancreatic cancer.

Highlights

The Warburg effect in cancer cells is the product of two factors, a return of cells to glycolytic metabolism and increased production of mitochondrial reactive oxygen species (ROS), which is due to alterations in oxidative phosphorylation [1]
The signaling pathway that leads to the activation of protein kinase D1 (PKD1) by oxidative stress seems unique because it involves tyrosine phosphorylation of the molecule at several residues [8, 10, 11], which do not occur when PKD1 is activated by receptor-mediated signaling [7]
The occurrence of increased oxidative stress in tumor cells requires ROS-sensing signaling to upregulate antioxidant systems to counterbalance ROS

Summary

Heike Döppler and Peter Storz*

Due to alterations in their metabolic activity and decreased mitochondrial efficiency, cancer cells often show increased generation of reactive oxygen species (ROS), but at the same time, to avoid cytotoxic signaling and to facilitate tumorigenic signaling, have mechanism in place that keep ROS in check This requires signaling molecules that convey increases in oxidative stress to signal to the nucleus to upregulate antioxidant genes. Protein kinase D1 (PKD1), the serine/threonine kinase, is one of these ROS sensors In this mini-review, we highlight the mechanisms of how PKD1 is activated in response to oxidative stress, so far known downstream effectors, as well as the importance of PKD1-initiated signaling for development and progression of pancreatic cancer

INTRODUCTION

PKD ACTIVATION DOWNSTREAM OF ROS

CONCLUSION