Salinomycin is a polyether
ionophore antibiotic having anti-tumorigenic property in various types of
cancer. Elevated
thymidine phosphorylase (TP) levels, a key
enzyme in the
pyrimidine nucleoside salvage pathway, are associated with an aggressive disease phenotype and poor prognoses.
Heat shock protein 90 (Hsp90) is a ubiquitous
molecular chaperone that is responsible for the stabilization and maturation of many oncogenic
proteins. In this study, we report whether Hsp90 inhibitor
17-AAG could enhance
salinomycin-induced cytotoxicity in NSCLC cells through modulating TP expression in two
non-small-cell lung cancer (NSCLC) cell lines, A549 and H1975. We found that
salinomycin increased TP expression in a MKK3/6-
p38 MAPK activation manner. Knockdown of TP using
siRNA or inactivation of
p38 MAPK by pharmacological inhibitor
SB203580 enhanced the cytotoxic and growth inhibition effects of
salinomycin. In contrast, enforced expression of MKK6E (a constitutively active form of MKK6) reduced the cytotoxicity and cell growth inhibition of
salinomycin. Moreover, Hsp90 inhibitor
17-AAG enhanced cytotoxicity and cell growth inhibition of
salinomycin in NSCLC cells, which were associated with down-regulation of TP expression and inactivation of
p38 MAPK. Together, the Hsp90 inhibition induced TP down-regulation involved in enhancing the
salinomycin-induced cytotoxicity in A549 and H1975 cells.