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Cell Stress and Chaperones

, Volume 23, Issue 3, pp 317–334 | Cite as

Role of the unfolded protein response in determining the fate of tumor cells and the promise of multi-targeted therapies

  • Kunyu Shen
  • David W. Johnson
  • David A. Vesey
  • Michael A. McGuckin
  • Glenda C. Gobe
Mini Review

Abstract

Although there have been advances in our understanding of carcinogenesis and development of new treatments, cancer remains a common cause of death. Many regulatory pathways are incompletely understood in cancer development and progression, with a prime example being those related to the endoplasmic reticulum (ER). The pathological sequelae that arise from disruption of ER homeostasis are not well defined. The ER is an organelle that is responsible for secretory protein biosynthesis and the quality control of protein folding. The ER triggers an unfolded protein response (UPR) when misfolded proteins accumulate, and while the UPR acts to restore protein folding and ER homeostasis, this response can work as a switch to determine the death or survival of cells. The treatment of cancer with agents that target the UPR has shown promising outcomes. The UPR has wide crosstalk with other signaling pathways. Multi-targeted cancer therapies which target the intersections within signaling networks have shown synergistic tumoricidal effects. In the present review, the basic cellular and signaling pathways of the ER and UPR are introduced; then the crosstalk between the ER and other signaling pathways is summarized; and ultimately, the evidence that the UPR is a potential target for cancer therapy is discussed. Regulation of the UPR downstream signaling is a common therapeutic target for different tumor types. Tumoricidal effects achieved from modulating the UPR downstream signaling could be enhanced by phosphodiesterase 5 (PDE5) inhibitors. Largely untapped by Western medicine for cancer therapies are Chinese herbal medicines. This review explores and discusses the value of some Chinese herbal extracts as PDE5 inhibitors.

Keywords

Endoplasmic reticulum stress Unfolded protein response Signaling pathways Cancer Phosphodiesterase 5 inhibitors 

Abbreviations

ASK

Apoptosis signal-regulating kinase

ATF

Activating transcription factor

cGMP

Cyclic guanosine monophosphate

eIF2

Eukaryotic translation initiation factor 2α

ERAD

Endoplasmic reticulum associated degradation

ERK

Extracellular signal-regulated kinase

FDA

Food and Drug Administration

GADD

Growth arrest and DNA-damage-inducible protein

GSK

Glycogen synthase kinase

GTP

Guanosine triphosphate

HIF

Hypoxia-inducible factor

HRD

3-hydroxyl-3-methylglutaryl-coenzymeA reductase degradation

IBTKα

inhibitor of Bruton’s tyrosine kinase

IFN

Interferon

IGF

Insulin-like growth factor

IL

Interleukin

I/R

Ischemia-reperfusion

IRE

Inositol-requiring enzyme

MAPK

Mitogen-activated protein kinase

MEF

Mouse embryonic fibroblasts

MHC

Major histocompatibility complex

mTOR

Mammalian target of rapamycin

NFκB

Nuclear factor κB

OSCC

Oral squamous cell carcinoma

OS-9

Osteosarcoma amplified 9

PDE

Phosphodiesterase

PDK

Phosphoinositide dependent kinase

PERK

Double-stranded RNA-activated protein kinase/PKR-like ER kinase

PIP3

Phosphatidylinositol-3,4,5-triphosphate

PKB

Protein kinase B

ROS

Reactive oxygen species

S6 K

S6 kinase

TCHM

Traditional Chinese herbal medicine

TFG-β

Transforming growth factor-β

t-PA

tissue-type plasminogen activator

TRAF

Tumor necrosis factor receptor associated factor

TRPC

Transient receptor potential cation channel

TNFR

Tumor necrosis factor receptor

UPR

Unfolded protein response

VEGF

Vascular endothelial growth factor

XBP

X-box binding protein

4E–BP

4E–binding protein

Notes

Acknowledgements

This work is partly supported by the scholarship from China Scholarship Council (File No. 2016008440278).

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Copyright information

© Cell Stress Society International 2017

Authors and Affiliations

  • Kunyu Shen
    • 1
  • David W. Johnson
    • 1
    • 2
    • 3
  • David A. Vesey
    • 2
    • 3
  • Michael A. McGuckin
    • 4
  • Glenda C. Gobe
    • 1
    • 3
  1. 1.Kidney Disease Research Group, UQ Diamantina Institute, Translational Research InstituteThe University of QueenslandBrisbaneAustralia
  2. 2.Department of Nephrology, Princess Alexandra HospitalBrisbaneAustralia
  3. 3.Centre for Health Services Research, Faculty of MedicineThe University of QueenslandBrisbaneAustralia
  4. 4.Mucosal Disease Inflammatory Disease Biology and Therapeutics Group, UQ Mater Research Institute, Translational Research InstituteThe University of QueenslandBrisbaneAustralia

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