title: Non-adherent culture induces paclitaxel resistance in H460 lung cancer cells via ERK-mediated up-regulation of βIVa-tubulin.
abstract: 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.
authors.affiliation: Applied Biological Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
authors.forename: Korakot
authors.initials: K
authors.lastname: Atjanasuppat
authors.affiliation: Applied Biological Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry of Education, Bangkok 10400, Thailand. Electronic address: kriengsak@cri.or.th.
authors.forename: Kriengsak
authors.initials: K
authors.lastname: Lirdprapamongkol
authors.affiliation: Applied Biological Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
authors.forename: Phatcharida
authors.initials: P
authors.lastname: Jantaree
authors.affiliation: Applied Biological Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Jisnuson
authors.initials: J
authors.lastname: Svasti
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D014404:Tubulin / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C582076:TUBB4A protein, human; D014404:Tubulin; D017239:Paclitaxel
keywords: Chemoresistance; Circulating tumor cells; Lung cancer; Metastasis; β-Tubulin isotypes