Doxorubicin-Induced TrkAIII Activation: A Selection Mechanism for Resistant Dormant Neuroblastoma Cells.
Lucia CappabiancaMichela SebastianoMarianna RuggieriMaddalena SbaffoneVeronica ZelliAntonietta Rosella FarinaAndrew Reay MackayPublished in: International journal of molecular sciences (2022)
Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The acquisition of Dox resistance, however, is a major barrier to a sustained response and leads to a poor prognosis in advanced disease states, reinforcing the need to identify and inhibit Dox resistance mechanisms. In this context, we report on the identification and inhibition of a novel Dox resistance mechanism. This mechanism is characterized by the Dox-induced activation of the oncogenic TrkAIII alternative splice variant, resulting in increased Dox resistance, and is blocked by lestaurtinib, entrectinib, and crizotinib tyrosine kinase and LY294002 IP3-K inhibitors. Using time lapse live cell imaging, conventional and co-immunoprecipitation Western blots, RT-PCR, and inhibitor studies, we report that the Dox-induced TrkAIII activation correlates with proliferation inhibition and is CDK1- and Ca 2+ -uniporter-independent. It is mediated by ryanodine receptors; involves Ca 2+ -dependent interactions between TrkAIII, calmodulin and Hsp90; requires oxygen and oxidation; occurs within assembled ERGICs; and does not occur with fully spliced TrkA. The inhibitory effects of lestaurtinib, entrectinib, crizotinib, and LY294002 on the Dox-induced TrkAIII and Akt phosphorylation and resistance confirm roles for TrkAIII and IP3-K consistent with Dox-induced, TrkAIII-mediated pro-survival IP3K/Akt signaling. This mechanism has the potential to select resistant dormant TrkAIII-expressing NB cells, supporting the use of Trk inhibitors during Dox therapy in TrkAIII-expressing NBs.
Keyphrases
- high glucose
- poor prognosis
- diabetic rats
- tyrosine kinase
- drug induced
- induced apoptosis
- signaling pathway
- cell proliferation
- stem cells
- long non coding rna
- drug delivery
- endothelial cells
- emergency department
- oxidative stress
- nitric oxide
- cell death
- cell cycle arrest
- pain management
- endoplasmic reticulum stress
- radiation therapy
- rectal cancer
- human health
- climate change
- smoking cessation
- cell cycle
- heat shock protein
- adverse drug