PKCδ-dependent Activation of the Ubiquitin Proteasome System is Responsible for High Glucose-induced Human Breast Cancer MCF-7 Cell Proliferation, Migration and Invasion

Abstract

Type 2 diabetes mellitus (T2DM) has contributed to advanced breast cancer development over the past decades.However, the mechanism underlying this contribution is poorly understood. In this study, we determined thathigh glucose enhanced proteasome activity was accompanied by enhanced proliferation, migration and invasion,as well as suppressed apoptosis, in human breast cancer MCF-7 cells. Proteasome inhibitor bortezomib (BZM)pretreatment mitigated high glucose-induced MCF-7 cell growth and invasion. Furthermore, high glucoseincreased protein kinase C delta (PKCδ)-phosphorylation. Administration of the specific PKCδ inhibitorrottlerin attenuated high glucose-stimulated cancer cell growth and invasion. In addition, PKCδ inhibition byboth rottlerin and PKCδ shRNA significantly suppressed high glucose-induced proteasome activity. Our resultssuggest that PKCδ-dependent ubiquitin proteasome system activation plays an important role in high glucoseinducedbreast cancer cell growth and metastasis.