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

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Cell Stress and Chaperones Aims and scope

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.

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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

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Acknowledgements

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

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Authors and Affiliations

  1. Kidney Disease Research Group, UQ Diamantina Institute, Translational Research Institute, The University of Queensland, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia

    Kunyu Shen, David W. Johnson & Glenda C. Gobe

  2. Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia

    David W. Johnson & David A. Vesey

  3. Centre for Health Services Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia

    David W. Johnson, David A. Vesey & Glenda C. Gobe

  4. Mucosal Disease Inflammatory Disease Biology and Therapeutics Group, UQ Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia

    Michael A. McGuckin

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  1. Kunyu Shen
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Correspondence to Glenda C. Gobe.

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Shen, K., Johnson, D.W., Vesey, D.A. et al. Role of the unfolded protein response in determining the fate of tumor cells and the promise of multi-targeted therapies. Cell Stress and Chaperones 23, 317–334 (2018). https://doi.org/10.1007/s12192-017-0844-3

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