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Review
. 2018 Apr;109(4):919-925.
doi: 10.1111/cas.13551. Epub 2018 Mar 23.

Roles of protein kinase R in cancer: Potential as a therapeutic target

Takao Watanabe  1 , Takeshi Imamura  2   3 , Yoichi Hiasa  1
Affiliations
Review

Roles of protein kinase R in cancer: Potential as a therapeutic target

Takao Watanabe et al. Cancer Sci. 2018 Apr.

Abstract

Double-stranded (ds) RNA-dependent protein kinase (PKR) is a ubiquitously expressed serine/threonine protein kinase. It was initially identified as an innate immune antiviral protein induced by interferon (IFN) and activated by dsRNA. PKR is recognized as a key executor of antiviral host defense. Moreover, it contributes to inflammation and immune regulation through several signaling pathways. In addition to IFN and dsRNA, PKR is activated by multiple stimuli and regulates various signaling pathways including the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. PKR was initially thought to be a tumor suppressor as a result of its ability to suppress cell growth and interact with major tumor suppressor genes. However, in several types of malignant disease, such as colon and breast cancers, its role remains controversial. In hepatocellular carcinoma, hepatitis C virus (HCV) is the main cause of liver cancer, and PKR inhibits HCV replication, indicating its role as a tumor suppressor. However, PKR is overexpressed in cirrhotic patients, and acts as a tumor promoter through enhancement of cancer cell growth by mediating MAPK or signal transducer and activator of transcription pathways. Moreover, PKR is reportedly required for the activation of inflammasomes and influences metabolic disorders. In the present review, we introduce the multifaceted roles of PKR such as antiviral function, tumor cell growth, regulation of inflammatory immune responses, and maintaining metabolic homeostasis; and discuss future perspectives on PKR biology including its potential as a therapeutic target for liver cancer.

Keywords: double-stranded (ds) RNA-dependent protein kinase (PKR); hepatitis C virus (HCV); hepatocellular carcinoma (HCC); interferon; mitogen-activated protein kinase (MAPK).

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Figures

Figure 1
Figure 1
Antiviral effects of double‐stranded RNA‐dependent protein kinase (PKR). Double stranded‐RNA produced by RNA viral replication and interferon are potent activators of PKR. Activated PKR induces PKR dimerization and PKR phosphorylation. Then, PKR phosphorylates eukaryotic initiation factor‐2 alpha (eIF2α), which inhibits protein synthesis, including that of virally encoded proteins. HCV, hepatitis C virus
Figure 2
Figure 2
Anti‐double‐stranded RNA‐dependent protein kinase (PKR) effects as a result of hepatitis C virus (HCV). HCV has developed PKR inhibitory strategies for their persistence. The NS5A of HCV‐1b with a wild‐type interferon sensitivity determining region (ISDR) sequence within the PKR‐binding domain has the potential to block the interferon (IFN)‐induced PKR that mediates various aspects of the antiviral effects. The E2 gene of HCV interacts with the PKR‐eukaryotic initiation factor‐2 alpha phosphorylation homology domain and inhibits PKR activation by IFN
Figure 3
Figure 3
Relationship between double‐stranded RNA‐dependent protein kinase (PKR) and hepatitis C virus (HCV). In patients with chronic HCV infection, HCV function against PKR is greater than the anti‐HCV function of PKR, so active inflammation is maintained. However, in liver cancer, PKR is overexpressed, and its functions dominate, resulting in cancer progression
Figure 4
Figure 4
Cancer suppression and progression effects of double‐stranded (ds) RNA‐dependent protein kinase (PKR). PKR influences liver cancer through mechanisms that function either against viral infection or through the growth of cancer cells. PKR during viral infection in hepatocytes or apoptotic effect shows its function of tumor suppression. In contrast, PKR acts as a tumor promoter through enhancement of cancer cell growth. Thus, PKR works as a molecular Jekyll and Hyde in liver cancer. eIF2α, eukaryotic initiation factor 2 alpha; HCV, hepatitis C virus; HSP, heat shock protein; IL, interleukin; IRF, interferon regulatory factor; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PACT, protein activator of interferon‐induced protein kinase; PDGF, platelet‐derived growth factor; STAT, signal transducer and activator of transcription; TLR4, Toll‐like receptor 4; TNFα, tumor necrosis factor alpha
Figure 5
Figure 5
Multi‐functional roles of double‐stranded RNA‐dependent protein kinase (PKR) against liver cancer. PKR has multifaceted roles in liver cancer including antiviral functions, promotion of tumor cell growth, regulation of the inflammatory immune response, induction of autophagy, and maintenance of metabolic homeostasis. PKR may be an attractive therapeutic target for human liver cancer. HMGB1, high mobility group box 1; LC3, light chain 3; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; STAT, signal transducer and activator of transcription
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