A Novel Role for BDNF-TrkB in the Regulation of Chemotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Abstract

Mechanisms of resistance for HNSCC to cisplatin (CDDP), the foundational chemotherapeutic agent in the treatment of this disease, remain poorly understood. We previously demonstrated that cisplatin resistance (CR) can be overcome by targeting Trk receptor. In the current study, we explored the potential mechanistic role of the BDNF-TrkB signaling system in the development of CDDP resistance in HNSCC. Utilizing an in vitro system of acquired CR, we confirmed a substantial up-regulation of both BDNF and TrkB at the protein and mRNA levels in CR cells, suggesting an autocrine pathway dysregulation in this system. Exogenous BDNF stimulation led to an enhanced expression of the drug-resistance and anti-apoptotic proteins MDR1 and XiAP, respectively, in a dose-dependently manner, demonstrating a key role for BDNF-TrkB signaling in modulating the response to cytotoxic agents. In addition, modulation of TrkB expression induced an enhanced sensitivity of cells to CDDP in HNSCC. Moreover, genetic suppression of TrkB resulted in changes in expression of Bim, XiAP, and MDR1 contributing to HNSCC survival. To elucidate intracellular signaling pathways responsible for mechanisms underlying BDNF/TrkB induced CDDP-resistance, we analyzed expression levels of these molecules following inhibition of Akt. Inhibition of Akt eliminated BDNF effect on MDR1 and Bim expression in OSC-19P cells as well as modulated expressions of MDR1, Bim, and XiAP in OSC-19CR cells. These results suggest BDNF/TrkB system plays critical roles in CDDP-resistance development by utilizing Akt-dependent signaling pathways.

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

“…TrkB plays important roles in differentiation, in proliferation, and mostly, in cell survival mediated through PLC, MAPK, or PI3K/Akt signaling in neurons [61]. Notably, TrkB has also been found to be associated with drug resistance in neuroblastoma [62,63] and head and neck squamous cell carcinoma [64]. Interestingly, TrkB downregulation after ectopic expression of miR-200c in doxorubicin-resistant breast cancer cells sensitizes the cells toward doxorubicin treatment.…”

BDNF: An Oncogene or Tumor Suppressor?

“…BDNF/TrkB overexpression (Table i) confers a migratory phenotype to tumor cells and primes cancer cells to resist substantial genotoxic stressors, most of which are front-line chemotherapies (4-6). BDNF-mediated activation of TrkB also results in RAs activation (7), in turn accelerating cell-cycle progression and presumably contributing to poor prognosis of patients with cancers dependent on the BDNF signaling pathway (8,9). BDNF and Trkb overexpression has also been shown to contribute to oncogenesis of aggressive neuroblastoma cells (10) and to post-chemotherapeutic recurrence of highly aggressive breast cancer stem cells (11), demonstrating that this signaling pathway seems to be ubiquitous in the progression of multiple cancers and dynamically regulates several aspects of tumor cell physiology.…”

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Tropomyosin related kinase B signaling Tropomyosin related kinases (Trks) are RTKs, which when stimulated by brain derived neurotrophic factor (BDNF) induce activation of various downstream pathways including Akt, Src, or MAPK resulting in cell proliferation, apoptosis resistance, and metastasis in human cancer models (Lee et al 2012). Both TrkB and BDNF are highly expressed in human EC as compared to the normal endometrium.…”