Factors Secreted by Human Neuroblastoma Mediate Doxorubicin Resistance by Activating STAT3 and Inhibiting Apoptosis

摘要: The transcription factor Stat3 has been reported to play a key role in protecting cells against apoptosis by up-regulating expression of the anti-apoptotic gene Bcl-xL. This investigation analyzes relationship between development resistance doxorubicin-mediated neuroblastoma (SKN-SH) and activation signaling pathway. A drug-resistant cell line (SKN-SH/Dox6) was generated continuous exposure incremental concentrations doxorubicin. Specific antibodies were utilized for Western blots confocal microscopy determine nuclear localization activated Stat3. Doxorubicin-mediated DNA fragmentation inhibited caspase-3 activity decreased SKN-SH/Dox6 cells. Up-regulation phosphorylation Bcl-xL expression, increased translocation phospho-Stat3, binding occurred only resistant AG490, an inhibitor JAK/Stat3 pathway, suggesting that regulation involved common mechanism. Activation contingent upon stimulation evoked ligands secreted Evidence support this hypothesis provided experiments which doxorubicin-sensitive SKN-SH preincubated with conditioned media obtained from doxorubicin-resistant treatment activation. It also rendered doxorubicin as demonstrated sharp decrease doxorubicin-induced degradation cytotoxic potency. These findings suggest may be mediated factor(s) are synthesized tumor response agents.