14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 94

14-3-3ζ. Inhibition of 14-3-3ζ restored sensitivity to CHOP (cyclophosphamide,
hydroxyl doxorubicin, vincristine/Oncovin ® , prednisone) chemotherapeutic regimen
and inhibition of Akt also has a similar effect (Maxwell et al., 2011). The advantages
of targeting 14-3-3ζ to control and inhibit cell proliferation and drug resistance is
obvious from this. A proteomic analysis of chemotherapy-sensitive and chemother-
apy-resistant ER+ invasive ductal carcinoma tissue samples has shown that several
14-3-3 proteins, for example γ, θ, δ, ε, may also be associated with drug resistance
(Hodgkinson et al., 2012). Although the mechanisms involved are not well under-
stood, it has been recognised that other pathways might be switched on in the course
of development of resistance to tamoxifen. Hh and PI3K/Akt signalling have been
suggested as possibilities (see p. 36). The activation of Hh signalling linked up with
PI3K/Akt has been demonstrated in tamoxifen-resistant breast cancer cell lines
(Ramaswamy et al., 2012).
Among other therapeutic approaches being attempted is the development
of 14-3-3 inhibitors that might directly attenuate the cell proliferation and tumour
promoting activity of these proteins or synergistically sensitise tumour cells to con-
ventional therapeutic agents. The strategy is based on interference with the interac-
tion of 14-3-3 proteins with their interacting counterparts. Zhao et al. (2011) have
shown that 4-[(2 Z )-2-[4-formyl-6-methyl-5-oxo-3-(phosphonatooxymethyl) pyridin-
2-ylidene] hydrazinyl] benzoate inhibited the binding of 14-3-3ζ to some of its sub-
strates. It may be noted here that 14-3-3ζ (also 14-3-3ε) can bind to many substrates
including IRS1 (Ogihara et al., 1997) and PKC and inhibit the function of both.
Corradi et al. (2010) and Mancini et al. (2011) have described another non-
peptide small molecule called BVO2 (Asinex, Moscow), which is said to inhibit the
docking of 14-3-3 to their targets. It can release c-Abl from binding with 14-3-3σ,
which allows nuclear translocation of c-Abl leading to the activation of pro-apoptotic
genes. BVO2 has been found to inhibit the proliferation of both imatinib-sensitive
and -resistant leukaemia cells. Equally this can lead to oncogenic activation of c-Abl.
Another way this can be achieved is by using competitive inhibitor R18 to dislodge
14-3-3 association with the pro-apoptotic transcription factor FOXO3a and induce
apoptosis (Dong et al., 2007b, 2008). The R18 peptide specifically inhibits 14-3-3
function but it is not isoform specific. The similarity in binding affinities suggests
a common binding site for R18 on 14-3-3 proteins (Wang et al., 1999). So the use
of this inhibitor would depend upon whether the suppressor or promoter isoform is
expressed. The potential value of R18 is underscored by the finding that R18 inhibits
the interaction of 14-3-3 with Raf-1. Raf-1, which is activated by phosphorylation in
response to mitogens, is a MAP3K kinase. It binds directly to membrane associated
GTPases and regulates many cellular functions, importantly promotes cell survival
by inhibiting apoptosis and promotes cell migration and invasion.
The 14-3-3 proteins function by recognising and binding to phosphorylated-
serine/threonine motifs on their target proteins and modulate the function of the tar-
get proteins. Dimerisation is essential for their interaction with substrate proteins.
Also dimerisation diminishes 14-3-3 susceptibility to phosphorylation (Ying et al.,
2003). Now the provision of liability to be phosphorylated at the dimer interface
blocks signalling function. Sphingosine and its analogue FTY720 both promote