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Gabriele et al. J Cancer Metastasis Treat 2018;4:17 I http://dx.doi.org/10.20517/2394-4722.2018.06 Page 9 of 17

translocation and activation; it was additionally reported that this kinase played an important role in the
development of castration-resistant disease state . Indeed, tyrosine kinase inhibitors targeting Src can inhibit
[115]
androgen-independent growth of prostate cancer cells, but did not induce significant apoptosis. Therefore,
an autophagy blocking strategy might significantly potentiate the effects of tyrosine kinase inhibitors as pro-
apoptotic inducers . In addition to cell migration, Src assists in tumor invasion through its regulation of matrix
[116]
metalloproteinases (MMPs) via degradation of the extracellular matrix. Another interaction that involves Src
in CaP is with steroid receptors. It has been demonstrated that in low androgen conditions, AR can activate
Scr in the cytoplasm, thereby triggering downstream signaling events independent of AR transcriptional and
DNA-binding activity [38,48] . In fact, DNA synthesis can be inhibited by Src (as a dominant negative factor) after
stimulation with low amount of androgens, but the Scr pathway can be bypassed with higher concentrations
of androgen coupled with AR over-expression. Scr in addition to binding with AR, if stimulated with estradiol,
can also interact with the estrogen receptor (ER) and thereby promote cell proliferation [38,49,50] : thus, it can be
hypothesized that Src serves as a scaffolding protein for the AR-ER complex.

Focal kinase (FAK) adhesion, in addition to migration and proliferation, may also be involved in angiogenesis
and apoptosis in CaP cells. There are evidence that FAK induces vascular endothelial growth factor
(VEGF) transcription in an ERK1/2-dependent, Rap1-dependent, and Raf-dependent but Ras-independent
manner [91-93] .

PTEN, a tumor suppressor gene with dual phosphatase activity, is part of the negative FAK regulators, and
is deleted in the aggressive CaP . The formation of the Lyn-PI3K-NEP complex can be regulated indirectly,
[94]
in a negative way, by FAK . ETK/BMX complex, discovered in 1994, belongs to the Tec family of NRTK .
[60]
[117]
In CaP, ETK is downstream of PI3K on the induction of the neuroendocrine differentiation following IL-6
stimulation in LNCaP cells . It is also know that it works as an anti-apoptotic factor. Ove-expression of
[118]
ETK leads to a resistance to apoptosis in CaP cells due to its interaction with PI3K . The activation of EKT
[118]
do not require PI3K . Rather, the interaction of ETK with p53 could be another mechanism of protection
[27]
against apoptosis . The introduction of ETK C-terminal fragment into PC-3 cells lead to apoptosis after
[119]
proteolytic cleavage of ETK by caspases . ETK is a signal transducer between SRC and AR downstream and
[120]
FAK upstream. However, ETK alone is not enough efficient to activate AR, since it requires to interacts with
Pim1 protein [117,121] .
Several studies have suggested that inhibition of HDAC in the progression of autophagy could be a new
way for treatments of prostate cancer . It is known that HDAC inhibitors are among the most promising
[122]
targeted anticancer agents and are potent inducers of growth arrest, differentiation, and autophagic cell death
of prostate cells . Very recently, Patra et al. developed a novel HDAC inhibitor (MHY219) that induced
[124]
[123]
cancer cell death and might be employed as a chemotherapy adjuvant in clinical studies. Similarly, other HDAC
inhibitors have been tested in prostate cancer studies [125-127] . In another recent contribution, Vallo et al. assayed
[122]
PXD101, a potent pan HDAC inhibitor, to prevent the onset of castration-resistant phenotype and to potentiate
hormonal therapy. A very interesting aspect is that there is a functional link between HDAC and liver X
receptors (LXRs) members of the nuclear receptor family that regulates intracellular lipid homeostasis .
[128]
As already mentioned, lipids play a complex role in the progression and maintenance of prostate cancer. In
fact, the increasing de novo synthesis of cholesterol and/or fatty acids is associated with the development of
prostate cancer. Therefore, by inhibiting HDAC it was possible to reduce the levels of intracellular cholesterol
and consequently it reduced the proliferation of tumor cells. Inhibitors HDCA and LXRs can, therefore,
inhibit the proliferation of tumor cells .
[128]
Currently, the only drug, approved to be applied in the chemotherapy of PCa, is docetaxel. Recently, a
new drug was introduced, Salen-MN, a novel type of synthetic reagent bionic and exerts remarkable
anticancer activities, but its effect is not been completely elucidated in PCa. In particular, treatment with
Salen-Mn inhibited growth in PC-3 and DU145 cells. Moreover, Salen-Mn in vitro administration induced