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2015 ; 10
(8
): e0135962
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8-Chloroadenosine Sensitivity in Renal Cell Carcinoma Is Associated with AMPK
Activation and mTOR Pathway Inhibition
#MMPMID26313261
Kearney AY
; Fan YH
; Giri U
; Saigal B
; Gandhi V
; Heymach JV
; Zurita AJ
PLoS One
2015[]; 10
(8
): e0135962
PMID26313261
show ga
The adenosine analog 8-chloroadenosine has been shown to deplete ATP and inhibit
tumor growth in hematological malignancies as well as in lung and breast cancer
cell lines. We investigated effects of 8-chloroadenosine on clear cell (cc) renal
cell carcinoma (RCC) cell lines. 8-chloroadenosine was effective against ccRCC
cell viability in vitro, with IC50 ranging from 2 ?M in the most sensitive CAKI-1
to 36 ?M in the most resistant RXF-393. Proteomic analysis by reverse-phase
protein array revealed that 8-chloroadenosine treatment leads to inhibition of
the mTOR pathway. In time-course experiments, 8-chloroadenosine treatment rapidly
activated AMPK, measured by AMPK and ACC phosphorylation, and subsequently caused
dephosphorylation of p70S6K and ribosomal protein RPS6 in the sensitive cell
lines. However, in the resistant cell lines, AMPK activity and the mTOR pathway
were unaffected by the treatment. We also noted that the resistant cell lines had
elevated basal levels of phospho RPS6 and AKT. Inhibition of PI3K pathway
enhanced the efficacy of 8-chloroadenosine across all cell lines. Our
observations indicate that 8-chloroadenosine activity is associated with
inhibition of the mTOR pathway, and that phospho RPS6 and PI3K pathway activation
status may determine resistance. Among solid tumors, RCC is one of the few
susceptible to mTOR inhibition. We thus infer that 8-chloroadenosine may be
effective in RCC by activating AMPK and inhibiting the mTOR pathway.