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A historical overview of protein kinase PKR… demonstrating the importance of PKR/eIF2a status in
cancer response to chemotherapy. Chemotherapeutic drugs
comparison with the control empty vector, suggesting the such as 5-Fluorouracil, doxorubicin and etoposide are able
potential of VV-PKR construction as an oncolytic vector to induce and activate PKR protein, triggering apoptosis
for cancer (137). A possible mechanism of evasion of PKR (22, 63, 131, 140).
activation has been suggested by some cancer cells that are
unable to induce apoptosis despite eIF2a phosphorylation However, evidence also suggests an antagonist role of
status (131). Moreover, it has been reported that PKR is PKR in cancer that has challenged the proposed function
suppressed or inactivated in some malignancies, and of PKR as a tumour suppressor. It is now well established
increased PKR expression has been shown to correlate that activation of PKR leads to the induction of pro-
with better prognosis in head and neck cancer, melanoma, survival as well as pro-death pathways whose balance
lung, and colon cancer (1, 131, 138, 139). Furthermore, depends on the intensity and nature of the activating
some evidence shows that PKR may act as a tumour stimulus as well as the activation or level of expression of
suppressor in leukemia and could play an important role in the PKR´s modulators (Figure 4).
haematological disorders (129, 131). Other evidence
supporting the antitumour role of PKR comes from studies

Figure 4. PKR plays an antagonist role in cancer. PKR activation can induce both pro-survival and pro-death pathways. The nature

and the intensity of activation stimuli as well as the level of expression of PKR´s modulators could decant the balance of consequences of

PKR activation. Understanding the cellular factors and signals that regulate PKR in the different diseases would be extremely valuable

from a clinical point of view.

In fact, it has been reported that PKR was the methodology employed.

overexpressed and linked with malignancy in thyroid 4.1.a. PKR involvement in the antiviral activity of several
carcinoma, broncheoalveolar carcinoma, colon, melanoma, tumour suppressors: p53, Arf, and Rb
lung, breast, liver cancers and some haematological
disorders (131, 141, 142). Moreover, PKR involvement An increasing number of tumour suppressor genes are
has been suggested in the neoplastic process of the induced by interferons and may play an important role in
proliferative transcription factor NF-kB (143). Curiously, the control of cell proliferation induced by this cytokine. In
the finding of different expression patterns of addition, pathways triggered by both tumour suppressors
PKR/eIF2a/NF-kB activity, even in the same type of and IFN converge as common targets for non-related
cancer, points to the complexity of the role of PKR in tumour viruses. The inhibition of the IFN response by
cancer (126). It is important to note that some clinical animal viruses is explained by the fundamental role that
studies related to PKR analysis did not follow a IFN plays to control virus infection. However, the reasons
standardised protocol, differing in the number of tumour why many viruses, including those that do not require the
samples analysed and in the inclusion criteria of patients, replication of the host, target tumour suppressor pathways
which makes it difficult to compare results between are varied and remain under investigation. In fact,
groups. This fact, together with the complexity of PKR oncogenic viruses frequently target the pathways
signalling and its regulation, highlights the need for controlled by tumour suppressor genes, suggesting an extra
consensus on a standardised protocol, specifying patient function for these proteins as antiviral factors.
inclusion criteria, the appropriate number of samples, and
The classical tumour suppressor induced by IFN is p53,

@Real Academia Nacional de Farmacia. Spain 155