Circulating tumor cells (CTCs) are metastasizing epithelial
cancer cells that adapt to survive when floating in bloodstream during
metastasis. This condition can be mimicked in vitro by using non-adherent cell culture. The chemosensitivity of CTCs appears to correlate with the response of metastatic
cancer patients to
therapy, but chemoresistance is also frequently observed in advanced stage
cancer patients, who have never previously received
chemotherapy. We hypothesize that adaptation of epithelial
cancer cells to become floating CTCs could lead to development of chemoresistance. Here, we explore whether chemoresistance is induced in epithelial
cancer cells when cultured under non-adherent conditions. Increased
paclitaxel-specific resistance was observed in floating cells compared to attached cells in H460, MCF-7, and HepG2 human
cancer cell lines, by 15.6-, 3.9-, and 2.6-fold increases in IC50 values, respectively. qRT-PCR analysis showed that a
paclitaxel-resistant β-
tubulin isotype, βIVa-
tubulin, was the most up-regulated gene compared with other β-
tubulin isotypes in H460 floating cells, concomitant with elevated ERK activation. ERK inhibitor treatment could attenuate the up-regulation of βIVa-
tubulin, and decreased the
paclitaxel resistance of H460 floating cells, even though other β-
tubulin isotypes were up-regulated when the ERK activation was blocked. In conclusion, we show induction of
paclitaxel resistance in epithelial
cancer cells, when floating in non-adherent culture, and this might occur with CTCs of
cancer patients.