RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells

Michael A. Skinner, Karen E. Lackey, Alex J. Freemerman

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2019-2025
Number of pages7
JournalAnticancer Research
Volume28
Issue number4 B
StatePublished - Jul 2008

Fingerprint

Doxorubicin
Apoptosis
Phosphotransferases
Mitogen-Activated Protein Kinases
Phosphorylation
Pharmaceutical Preparations
Protein-Serine-Threonine Kinases
Protein Kinase Inhibitors
Transfection
Protein Isoforms
Drug Therapy
Genes
Neoplasms
Medullary Thyroid cancer

Keywords

  • Apoptosis
  • Doxorubicin
  • MAPK pathway
  • Medullary thyroid cancer
  • RET

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Skinner, M. A., Lackey, K. E., & Freemerman, A. J. (2008). RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells. Anticancer Research, 28(4 B), 2019-2025.

RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells. / Skinner, Michael A.; Lackey, Karen E.; Freemerman, Alex J.

In: Anticancer Research, Vol. 28, No. 4 B, 07.2008, p. 2019-2025.

Research output: Contribution to journalArticle

Skinner, MA, Lackey, KE & Freemerman, AJ 2008, 'RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells', Anticancer Research, vol. 28, no. 4 B, pp. 2019-2025.
Skinner MA, Lackey KE, Freemerman AJ. RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells. Anticancer Research. 2008 Jul;28(4 B):2019-2025.
Skinner, Michael A. ; Lackey, Karen E. ; Freemerman, Alex J. / RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells. In: Anticancer Research. 2008 ; Vol. 28, No. 4 B. pp. 2019-2025.
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N2 - 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.

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