Abstract
Background: Medullary thyroid cancer (MTC) is generally resistant to chemotherapy and the frequent constitutive activation of RET (rearranged during transfection gene) in these tumors might inhibit drug-induced apoptosis. Materials and Methods: Each RET isoform was separately expressed in SK-N-MC cells (neural crest-derived tumor) and the impact of RET activation on doxorubicin-induced apoptosis was examined. Results: The activation of RET9 and RET51 in the SK-N-MC cells significantly reduced the doxorubicin-induced apoptosis by 50%, compared to untreated cells. RET activation also induced phosphorylation of ERK (extracellular regulated kinase), but no changes in AKT (serine/threonine kinase) phosphorylation were noted. In the presence of a MAP (mitogen-activated protein) kinase inhibitor or a RET kinase inhibitor, the RET-activated/drug-treated cells displayed nearly 75% and 100% of the doxorubicin-induced apoptosis of the drug-treated cells without RET activation, respectively. Conclusion: In SK-N-MC cells, downstream activation of MAP kinase, by both RET9 and RET51, appears to mediate the majority of RET-dependent resistance to chemotherapeutically induced apoptosis. MTC might be rendered more responsive to chemotherapeutic agents by the co-administration of a RET kinase inhibitor.
Original language | English (US) |
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Pages (from-to) | 2019-2025 |
Number of pages | 7 |
Journal | Anticancer Research |
Volume | 28 |
Issue number | 4 B |
State | Published - Jul 2008 |
Keywords
- Apoptosis
- Doxorubicin
- MAPK pathway
- Medullary thyroid cancer
- RET
ASJC Scopus subject areas
- Oncology
- Cancer Research