We recently showed that inhibition of
heat shock protein 90 (Hsp90) decreases
tumor growth and angiogenesis in
gastric cancer through interference with oncogenic signaling pathways. However, controversy still exists about the antimetastatic potential of Hsp90 inhibitors. Moreover, in vitro studies suggested that blocking Hsp90 could overcome p53-mediated resistance of
cancer cells to
oxaliplatin. We therefore hypothesized that blocking oncogenic signaling with a Hsp90 inhibitor would impair metastatic behavior of
colon cancer cells and also improve the efficacy of
oxaliplatin in vivo. Human
colon cancer cells (HCT116, HT29, and SW620) and the Hsp90 inhibitor
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were used for experiments. In vitro,
17-DMAG substantially inhibited phosphorylation of
epidermal growth factor receptor, c-Met, and
focal adhesion kinase, overall resulting in a significant decrease in
cancer cell invasiveness. Importantly,
17-DMAG led to an up-regulation of the
transcription factor activating transcription factor-3, a
tumor suppressor and antimetastatic factor, on
mRNA and
protein levels. In a cell death ELISA,
17-DMAG markedly induced apoptosis in both p53-wt and p53-deficient cells. In vivo,
17-DMAG significantly reduced
tumor growth and vascularization. Furthermore, blocking Hsp90 reduced hepatic
tumor burden and metastatic nodules in an experimental model of hepatic
colon cancer growth. Importantly, combining
oxaliplatin with
17-DMAG in vivo significantly improved growth inhibitory and proapoptotic effects on p53-deficient cells, compared with either substance alone. In conclusion, inhibition of Hsp90 abrogates the invasive properties of
colon cancer cells and modulates the expression of the antimetastatic factor
activating transcription factor-3. Hence, targeting Hsp90 could prove valuable for treatment of advanced
colorectal cancer by effectively inhibiting
colon cancer growth and hepatic
metastasis and improving the efficacy of
oxaliplatin.