In:
Journal of Cellular and Molecular Medicine, Wiley, Vol. 18, No. 7 ( 2014-07), p. 1460-1466
Abstract:
Molecular tumour targeting has significantly improved anti‐cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of R apamycin (m TOR ) and histone deacetylase ( HDAC ) inhibition has been shown not only to enhance anti‐tumour potential, but also to prevent resistance development seen under mono‐drug therapy. This investigation was designed to evaluate whether cross‐communication exists between m TOR signalling and epigenetic events regulated by HDAC . DU ‐145 prostate cancer cells were treated with insulin‐like growth factor ( IGF ) to activate the Akt‐m TOR cascade or with the HDAC ‐inhibitor valproic acid ( VPA ) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, m TOR , Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between m TOR and the epigenetic machinery. IGF activated m TOR , Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGF r blockade and knock‐down blocked the Akt‐m TOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up‐regulated histone acetylation, but also activated m TOR ‐Akt signalling. HDAC 1 and 2 knock‐down revealed that the interaction with the m TOR system is initiated by histone H3 acetylation. HDAC ‐m TOR communication, therefore, is apparent whereby tumour‐promoting (Akt/m TOR high , aH3/aH4 low ) and tumour‐suppressing signals (Akt/m TOR low , aH3/aH4 high ) are activated in parallel. Combined use of an HDAC ‐ and m TOR inhibitor might then diminish pro‐tumour effects triggered by the HDAC ‐ (Akt/m TOR high ) or m TOR inhibitor (aH3/aH4 low ) alone.
Type of Medium:
Online Resource
ISSN:
1582-1838
,
1582-4934
DOI:
10.1111/jcmm.2014.18.issue-7
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2076114-4
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