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Equivocal, explicit and emergent actions of PKC isoforms in cancer

Nature Reviews Cancer volume 21, pages 51–63 (2021)Cite this article

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Abstract

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.

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Fig. 1: Domain organization, activation and downregulation pathways for the PKC family.
Fig. 2: Biomarkers of PKC action and inaction.
Fig. 3: Cell cycle controls and PKC.

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Acknowledgements

The authors thank A. Fields and M. Reyland for commenting on the manuscript. They also acknowledge support from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001130), the UK Medical Research Council (FC001130) and the Wellcome Trust (FC001130). M.L. is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre (no grant numbers apply).

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  1. Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK

    Peter J. Parker, Sophie J. Brown, Veronique Calleja, Mathias Cobbaut, Jacqueline J. T. Marshall, Silvia Martini & Lisa Watson

  2. School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Campus, London, UK

    Peter J. Parker

  3. Bioinformatics, The Francis Crick Institute, London, UK

    Probir Chakravarty

  4. UCL Cancer Institute, University College London, London, UK

    Mark Linch

  5. Signalling and Structural Biology Laboratory, Francis Crick Institute, London, UK

    Neil Q. McDonald

  6. Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, UK

    Neil Q. McDonald

  7. Centre for Cancer Genomics and Computational Biology, Bart’s Cancer Institute, London, UK

    Tanya Soliman

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P.J.P. contributed to all aspects of the article. V.C., M.L. and P.C. contributed to researching data for the article and reviewing and/or editing the manuscript before submission. S.J.B., M.C., J.J.T.M., S.M., N.Q.M., T.S. and L.W. contributed to writing the article and reviewing and/or editing it before submission.

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Related links

cBioPortal: https://www.cbioportal.org

FDA orphan status was designated to bryostatin: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm

PKC412 in acute myeloid leukaemia: https://clinicaltrials.gov/ct2/results?cond = AML&term = PKC412

PKC412 in myelodysplastic syndrome: https://clinicaltrials.gov/ct2/results?cond = MDS&term = PKC412

Tigilanol tiglate: https://www.ema.europa.eu/en/medicines/veterinary/EPAR/stelfonta

Supplementary information

Glossary

1,2-diacylglycerol

(DAG). A neutral lipid component of membranes, serving in the biosynthesis of more complex lipids and as a signalling lipid.

Conformer

Used in a generic manner to indicate a particular protein conformation.

MMTV-ERBB2 transformation model

A transgenic mouse model with expression of the receptor tyrosine kinase ERBB2 under the control of the mammary gland selective MMTV promoter.

Bryostatins

Trace bioactive cyclic polyketides first identified in marine bryozoan Bugula neritina; they likely originate from the symbiont B. neritina.

Epoxytiglianes

Bioactive compounds originally identified in the kernels of Fontainea picrosperma fruits and related to phorbol esters (tigliane family of diterpenes).

Private mutations

Those rare mutations that appear only once in cancer genomes, that is, are private to that patient.

Topoisomerase 2α

(Topo2α). One of two genes in mammals that catalyse the resolution of intertwined, catenated DNA, through double-strand cutting, strand passage and religation reactions.

Borealin

One of the components of the chromosome passenger complex (CPC), alongside INCENP and survivin, regulating the localization and activity of the co-associated Aurora B, which completes the CPC.

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Parker, P.J., Brown, S.J., Calleja, V. et al. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer 21, 51–63 (2021). https://doi.org/10.1038/s41568-020-00310-4

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