Clinical science (1979), 2015-11, Vol.129 (9), p.809-822
2015
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- Autor(en) / Beteiligte
- Titel
- The Hedgehog signalling pathway mediates drug response of MCF-7 mammosphere cells in breast cancer patients
- Ist Teil von
- Clinical science (1979), 2015-11, Vol.129 (9), p.809-822
- Ort / Verlag
- England
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- BCSCs (breast cancer stem cells) have been shown to be resistant to chemotherapy. However, the mechanisms underlying BCSC-mediated chemoresistance remain poorly understood. The Hh (Hedgehog) pathway is important in the stemness maintenance of CSCs. Nonetheless, it is unknown whether the Hh pathway is involved in BCSC-mediated chemoresistance. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain BCSC-enriched MCF-7 MS (MCF-7 mammosphere) cells. We showed that MCF-7 MS cells are sensitive to salinomycin, but not paclitaxel, distinct from parent MCF-7 cells. The expression of the critical components of Hh pathway, i.e., PTCH (Patched), SMO (Smoothened), Gli1 and Gli2, was significantly up-regulated in MCF-7 MS cells; salinomycin, but not paclitaxel, treatment caused a remarkable decrease in expression of those genes in MCF-7 MS cells, but not in MCF-7 cells. Salinomycin, but not paclitaxel, increased apoptosis, decreased the migration capacity of MCF-7 MS cells, accompanied by a decreased expression of c-Myc, Bcl-2 and Snail, the target genes of the Hh pathway. The salinomycin-induced cytotoxic effect could be blocked by Shh (Sonic Hedgehog)-mediated Hh signalling activation. Inhibition of the Hh pathway by cyclopamine could sensitize MCF-7 MS cells to paclitaxel. In addition, salinomycin, but not paclitaxel, significantly reduced the tumour growth, accompanied by decreased expression of PTCH, SMO, Gli1 and Gli2 in xenograft tumours. Furthermore, the expression of SMO and Gli1 was positively correlated with the expression of CD44+ / CD24-, and the expression of SMO and Gli1 in CD44+ / CD24- tissues was associated with a significantly shorter OS (overall survival) and DFS (disease-free survival) in breast cancer patients receiving chemotherapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0143-5221eISSN: 1470-8736DOI: 10.1042/CS20140592Titel-ID: cdi_pubmed_primary_26201092
- Format
- –
- Schlagworte
- Animals, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, Breast Neoplasms - drug therapy, Breast Neoplasms - genetics, Breast Neoplasms - metabolism, CD24 Antigen - metabolism, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Female, Gene Expression Regulation, Neoplastic - drug effects, Hedgehog Proteins - metabolism, Humans, Hyaluronan Receptors - metabolism, Kaplan-Meier Estimate, Kruppel-Like Transcription Factors - genetics, Kruppel-Like Transcription Factors - metabolism, MCF-7 Cells, Mice, Inbred BALB C, Mice, Nude, Neoplastic Stem Cells - drug effects, Neoplastic Stem Cells - metabolism, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Paclitaxel - pharmacology, Paclitaxel - therapeutic use, Proto-Oncogene Proteins c-bcl-2 - genetics, Proto-Oncogene Proteins c-bcl-2 - metabolism, Proto-Oncogene Proteins c-myc - genetics, Proto-Oncogene Proteins c-myc - metabolism, Pyrans - pharmacology, Pyrans - therapeutic use, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - metabolism, Signal Transduction, Smoothened Receptor, Spheroids, Cellular - drug effects, Spheroids, Cellular - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism, Xenograft Model Antitumor Assays, Zinc Finger Protein GLI1, Zinc Finger Protein Gli2