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Ibrahim et al ALDHs and prostate cancer

studies have shown that e.g. the ALDH1A1 isoform relaxed by the action of histone acetyltransferase
positively correlates with the expression of CSC (HAT) or methyltransferase activity [143] , facilitating
surface markers CD133 [116] and CD34 [117] with utility the recruitment of transcriptional machinery which
in characterising liver CSCs and leukaemia SCs, stimulates RA responsive gene transcription [144,145] .
respectively. The association of ALDH3A1 has also
been reported in PCa progression [61] . Stem cell-like The RA biosynthetic pathway is likely to be
cells from DU145 cells have elevated expression of suppressed or activated depending on the local
ALDH3A1 compared to non-stem counterparts, and prostate microenvironment [146-148] . The effect of RA
the stem cell-like population generated xenograft has been investigated in normal and malignant
tumours with aggressive features [118] . prostate tissues [129,149] . Differential expression of RA
was demonstrated in normal prostate, BPH, and
ALDHS AND THE RETINOID SIGNALLING prostate carcinoma tissues [129] . For example it was
PATHWAY found that endogenous retinol levels were 2-fold
elevated in BPH compared to normal and PCa tissue
while RA levels were found 5-8 times lower in PCa
Retinoic acid (RA, all-trans retinoic acid (ATRA), tissue compared with the other two tissues. The
tretinoin) the physiologically active metabolite of authors speculated that the reason for this elevated
vitamin A (retinol) is a potent regulator of signalling level of retinol in BPH could reflect (1) a reduced
pathways during embryonic development [119] . RA activity of the dehydrogenase that metabolises retinol
is necessary for adult tissue homeostasis and acts to retinal or (2) uptake from serum that metabolises
through nuclear retinoic acid receptors (RARs) [120] , retinol to retinal. A possible cause for the reduced
with diverse immune modulatory roles [121,122] , role in level of RA in PCa could be a more rapid degradation
spermatogonial differentiation [123] , and cancer [124-126] . of RA by cytochrome P450 enzymes [150] .
RA is endogenously produced from retinol (vitamin A)
in two subsequent metabolic steps [Figure 1]: the first In addition, RA also has variable effects on PCa
step is the retinol oxidation to retinaldehyde, which is signalling pathways, either directly or indirectly by
catalysed by several alcohol dehydrogenases (also regulating certain transcriptional factors such as
known as retinol dehydrogenases) [127,128] . The second NR2F1 [151] and RA receptor responder 1 (RARR1) [152]
step is the oxidation of retinaldehyde to retinoic acid, since RA represses invasion and SC phenotype by
which is an irreversible step carried out by ALDHs induction of metastasis suppressors RARR1 and
(also known as retinal dehydrogenases) [129] . At least latexin (LXN) in PCa [153] .
four ALDH isoforms, ALDH1A1, 1A2, 1A3 and 8A1,
have been shown to be responsible for the oxidative Retinoids are used as cancer treatment, in part due
formation of retinol to RA [128,130-132] . ALDH1A3 to their ability to induce differentiation and arrest
appears to be the most catalytically efficient enzyme proliferation. In the clinic, RA has been clinically
for RA oxidation and has no apparent capacity to investigated in PCa as single treatment [154] , or with
metabolise cis-retinal substrates [133] . The involvement other agents in attempts to produce synergistic
of ALDHs in RA synthesis underpins their vital effects [155-157] . However, delivery of retinoids presents
function in pathways associated with cell proliferation, a challenge because of the rapid metabolism and the
differentiation and survival [87] . epigenetic alterations that can render cells retinoid
resistant [158] . This poses new challenges rather than
The synthesised RA binds to nuclear RAR and solutions. ALDH1A3 expression is regulated by many
retinoid X receptor (RXR) forming a heterodimeric factors and is linked to many metabolic pathways
complex, which binds to RA response elements including glycolysis and retinoid signalling, which
(RAREs), leading to downstream regulation of gene has been recently reviewed [87] and hence not further
expression and cell differentiation events [134-137] . RA discussed here.
and 9-cis-RA (isotretinoin) bind to RARs, whereas
only 9-cis-RA can bind to RXRs [23] . In response to The relationship between AR and ALDH1A3 has
RA synthesis, cellular retinoic acid binding protein been studied in both normal and tumour tissues, to
(CRABP) shuttles RA to the nucleus where it binds to understand the exact mechanism of their interaction,
the RAR/RXR heterodimer [138,139] . This subsequently and its relationship to the role of ALDH1A3 as a
results in the dissociation of co-repressors NCoR, marker of CSCs in several tumour types. In breast
SMRT and HDAC complex [140] and allows co- cancer, a potential link between ALDH1A3 expression
activators such as SRC/p160 family, p300/CBP and and RA signalling contributed to an increase in the
CARM-1 to bind [141,142] . The chromatin structure is rate of cancer progression [159] . In human epidermal

Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018 5