Proteasome regulators in pancreatic cancer

Abstract

Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.

Probing the Molecular Function of Novel Boron-containing Compounds

“…The ubiquitin-proteasome system is involved in several physiological processes, including regulating proteins involved in the progression of the cell cycle, transcription, translation, cell signaling and apoptosis 149 . Proteasomes work to regulate the normal protein turnover associated with normal metabolic conditions by selectively identifying targets in a multi-step ubiquitination process 165 . This ubiquitin "tag" identifies a protein that is subsequently degraded by the 26S proteasome 147 .…”

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

“…Hyaluronic acid, a key proteoglycan, enhances stromal rigidity and interstitial pressure, facilitating tumor progression and metastasis . Proteases play a pivotal role in cancer tissue remodeling, which is a complex process involving the degradation and reconstruction of the ECM and the modulation of cell and ECM interactions. , Matrix metalloproteinases (MMPs), secreted by myofibroblasts or tumor cells, particularly degrade ECM components, promoting vascular permeability, angiogenesis, and tumor invasion . In addition to MMPs, other protease families such as the serine proteases and cathepsins also contribute to tissue remodeling in cancer …”

Systemic treatment for advanced pancreatic cancer

“…Bortezomib, carfilzomib, and ixazomib are examples of proteasome inhibitors. These inhibitors kill pancreatic cancer cells by inducing apoptosis via endoplasmic reticulum stress; proapoptotic proteins and their anti-apoptotic target genes are upregulated, whereas numerous anti-apoptotic proteins, as well as signal transducers and transcription activators, are suppressed[ 33 , 34 ]. There was only one randomized study to assess the RR of tumor for bortezomib (PS-341) alone vs RR and the survival rate at 6 mo for the combination of bortezomib and gemcitabine in 85 patients with advanced pancreatic cancer.…”