RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells
Michael A Skinner1, Karen E Lackey, Alex J Freemerman
1Department of Pediatric Surgery, Children's Medical Center of Dallas, Dallas, TX 75235, USA.
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.
Related Concept Videos
The Intrinsic Apoptotic Pathway
Inhibition of Cdk Activity
Inhibition of CDK Activity
Targeted Cancer Therapies
There are several types of targeted therapies against specific...
The Extrinsic Apoptotic Pathway
Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
