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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 5 of 17

reaction that requires Atg7 and Atg10. The Atg12-Atg5 complex then interacts non-covalently with Atg16
to form a larger complex. LC3/Atg8 is cleaved at its C-terminus by Atg4 protease to generate the cytosolic
LC3-I. LC3-I is then conjugated to phosphatidylethanolamine following an ubiquitin like reaction that
requires Atg7 and Atg3. Then, the lipidated form of LC3, known as LC3-II, is attached to the autophagosome
membrane.

An extensive crosstalk and a dynamic balance exists between apoptosis and autophagy. Autophagy is a survival
mechanism that typically is switched on during a nutrient deficiency; however, its excessive activation can
lead to cell death, with morphological features different from apoptosis ones. Proteins typically placed at the
cross roads of this processes are Beclin-1 and Bcl-2. In particular, Beclin-1-dependent autophagy is inhibited
by Bcl-2, which works as an anti-autophagic regulator and as a pro-survival mechanism . Autophagy, like
[58]
other metabolic pathways, can be regulated by various inducers and inhibitors. For example, autophagy
can be induced by deprivation of amino acids or serum, whereas it can be reduced by 3-methyladenine
(3-MA), an inhibitor of class III PI3K, that blocks the generation of phosphatidylinositol 3-phosphate (PI3P),
an essential docking molecule for the formation of phagophores at early stage of autophagy. In addition,
to investigate the autophagic flux some antibiotics are used such as bafilomycin A1 and concanamycin A,
because they inhibit specific ATPase activities and acidification of the lysosome, and therefore the final
fusion event between the lysosomes and autophagic vesicles .
[58]

The process of autophagy has been identified as an important mechanism of cellular resistance, or alternatively
of cell death [59,60] . Autophagy is a response to the cell's energy demand, whereby the loose cytoplasm and the
cellular organelles undergo lysosomal degradation to compensate for the demand for alternative energy
during periods of nutritional limitation. Besides the recycling of nutrients, autophagy also plays a role for
degradating damaged organelles by proteolysis to maintain a cellular quality control.

A combined inhibition of autophagy and proteasome degradation pathway induces an accumulation of
intracellular protein aggregates reminiscent of neuronal inclusion bodies, causing a significant cancer cell
death than blocking the proteasome degradation pathway alone. As a result, proteasome inhibition activates
autophagy via a eukaryotic initiation 2 alpha-dependent mechanism to eliminate protein aggregates and
alleviate proteotoxic stress . On the other hand, sustained autophagy under conditions of protracted
[61]
starvation has also been proposed to lead to cell death; thus, the survival or death consequences of autophagy
are condition-dependent [62-65] . Therefore, in cancer, autophagy has a controversial role, it can protect cancer
cells from adverse conditions or induce the death of cancer cells. In particular, in human prostate cancer,
autophagy is often impaired due to allelic loss of Beclin-1 locus or to the activation of the PI3K kinase/
[66]
Akt/mTOR pathway that finally inhibits autophagy. It has been demonstrated, in particular in in vitro
studies on epithelial prostate cancer cells, that autophagy can provide a survival mechanism for cells that
are undergoing some kind of starvation, favoring tumor growth .
[67]

Autophagy in prostate cancer
As molecular events, cancer development is often associated with deletion or silencing of tumor suppressors
genes such as PTEN, a negative regulator of the PI3K/Akt/mTOR pathway , leading to resistance to
[68]
various therapies in both preclinical and clinical trials . Therefore, the PI3K/Akt/mTOR pathway plays a
[69]
central role in various cellular processes, including protein cell survival, motility, synthesis, cell cycle, cell
growth, and angiogenesis. The deregulation on this pathway may contribute to the malignant phenotype.
Many small-molecule inhibitors targeting Akt, mTOR, and/or PI3K, and typically promotes growth arrest
rather than cell death in solid tumors, and, therefore, use of small molecule inhibitors have been limited .
[70]
However, some of them have been successfully used in prostate cancer therapeutic schemes. In particular,
some prostate cancer cell lines such as PC346-Flu1 and LNCaP were sensitive to monotherapy with the novel
AKT inhibitor AZD5363, resulting in an increase in apoptosis at concentrations achievable in preclinical