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


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.


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



Apoptosis signal-regulating kinase


Activating transcription factor


Cyclic guanosine monophosphate


Eukaryotic translation initiation factor 2α


Endoplasmic reticulum associated degradation


Extracellular signal-regulated kinase


Food and Drug Administration


Growth arrest and DNA-damage-inducible protein


Glycogen synthase kinase


Guanosine triphosphate


Hypoxia-inducible factor


3-hydroxyl-3-methylglutaryl-coenzymeA reductase degradation


inhibitor of Bruton’s tyrosine kinase




Insulin-like growth factor






Inositol-requiring enzyme


Mitogen-activated protein kinase


Mouse embryonic fibroblasts


Major histocompatibility complex


Mammalian target of rapamycin


Nuclear factor κB


Oral squamous cell carcinoma


Osteosarcoma amplified 9




Phosphoinositide dependent kinase


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




Protein kinase B


Reactive oxygen species

S6 K

S6 kinase


Traditional Chinese herbal medicine


Transforming growth factor-β


tissue-type plasminogen activator


Tumor necrosis factor receptor associated factor


Transient receptor potential cation channel


Tumor necrosis factor receptor


Unfolded protein response


Vascular endothelial growth factor


X-box binding protein


4E–binding protein



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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