PDCD4 (Programmed Cell Death 4) - Therapeutic Strategies in Cancer Biology and Pathology - page 186

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PDCD4 (Programmed Cell
Death 4)

Another important tumour suppressor gene which functions as a cell proliferation
regulator and which is downregulated or inactivated in expression in many tumours is
PDCD4 (programmed cell death 4). PDCD4 can regulate both genetic transcription
and the process of translation of the message. The protein is phosphorylated and regu-
lated by Akt at two Akt/S6K phosphorylation sites, one N-terminal and one C-terminal.
Phosphorylation induces nuclear translocation of PDCD4, but PDCD4 is redistributed
in the cytoplasm if its phosphorylation is inhibited. Nuclear accumulation of c-Jun
reflects target gene activity in terms of induction of apoptosis. Although c-Jun phos-
phorylation might not be an absolute requirement for its translocation to the nucleus,
PI3K/Akt-mediated phosphorylation does regulate nuclear translocation and AP-1-
mediated transcription activity of PDCD4. Given the distribution of c-Jun in the nucleus
and JNK-1 in the cytoplasm, it is postulated that the basis of functional differentiation
arising from intracellular distribution is that whereas nuclear PDCD4 inhibits c-Jun by
directly interacting with it, in the cytoplasm PDCD4 inhibits JNK-1 and prevents it from
phosphorylating c-Jun (Palamarchuk et al., 2005). PDCD4 interacts with the eukary-
otic translation initiation factors eIF4AI and eIF4AII and co-localises with eIF4A in the
cytoplasm. Regulation of translation is mediated by interaction with initiation factors
eIF4A and eIF4G via the two tandem highly conserved helical MA3 domains each con-
sisting of about 130 amino acid residues (Waters et al., 2007; Yang et al., 2003a).
PDCD4 shows loss of expression in a number tumour cell lines; reduction in
protein correlated with that of the mRNA, although not invariably. Loss of PDCD4
expression was described in lung tumour cell lines and in a large number of tumour
samples. The loss occurred in a majority of the samples and associated with high
tumour grade and stage and corresponded with poor prognosis (Chen et al., 2003b).
Downregulation of PDCD4 mRNA and protein has been encountered in 2/3 gastro-
intestinal stromal tumours and correlated with proliferation Ki-67 index, which more
than halved in high PDCD4 expressing tumours (Ding et al., 2012). The authors do
claim that loss of expression is greater in the so-called risk group, but they do not
define what they mean by risk groups, how the risk factor is determined or assessed.
The suppressor function of the gene might be achieved via the operation several
signalling pathways. The transcription factor myc regulates several pathways lead-
ing to cell proliferation, cell cycle regulation and apoptosis. Myc induces Ras/MAPK
signalling. Inhibition of the activation of MAPK suppresses the oncogenic action of
c-myc (Gramling and Eischen, 2012). The suppressor function of PDCD4 might flow
from its ability to inhibit MAPK signalling. Suppression of PCDC4 seems to result
in the upregulation of MAP4K1, which is also increased by c-myc overexpression
(Wang et al., 2012a). The anti-proliferative, pro-apoptosis function and suppression of