Background Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that
arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy,
the prognosis remains poor. Because of its locally advanced nature, cisplatin-based
induction chemotherapy has been used in our institution to downstage locoregionally
advanced tumors before definitive surgery or radiation therapy. Unfortunately, nearly
50% of SNUC patients do not respond to induction chemotherapy, and this event is associated
with poor survival rate. Therefore, developing strategies to overcome resistance to
induction chemotherapy is crucial. Our previous gene expression analysis in specimens
harvested from responders and nonresponders to induction chemotherapy showed that
the TGFβ signaling pathway might be activated in the nonresponders. In this study,
we examined the mechanism of TGFβ activation in nonresponders by using a SNUC cell
line derived from one of those nonresponders. We also investigated whether inhibition
of the TGFβ signaling pathway would be able to concur chemoresistance in the SNUC
cell line.
Methods The MDA8788–6 cell lines established from a nonresponder to induction chemotherapy
was used in this study. Activation of the TGFβ signaling pathway was accessed by phosphorylation
of SMAD2. Two commercially available TGFβ receptor I (TGFßRI/ALK5) inhibitors LY2157299
and EW-7197 were used to inhibit the pathway. The cell line was also treated by serum-free
conditioned medium collected from the same cell line to explore the mechanisms of
the TGFβ signaling activation. Cell growth and cell survival were evaluated by Hoechst
33342 staining and clonogenic assay, previously.
Results First, basal level of TGFβ signaling was assessed by phosphorylation of SMAD2 under
the condition of serum starvation. Interestingly, phosphorylation of SMAD2 was enhanced
by serum starvation and the TGFβ1 ligand did not increase the signal further. This
phosphorylation of SMAD2 by serum starvation was inhibited by the TGFßRI (ALK5) inhibitors
LY2157299 and EW-7197 indicating the phosphorylation of SMAD2 went through TGFßRI.
The SNUC cell line treated with conditioned media collected from the same cell line
also induced the TGFβ signaling pathway, indicating this activation may occur in an
autocrine manner. Treatment of the cells with the TGFßRI inhibitor successfully showed
inhibition of growth and survival combined with cisplatin.
Conclusion Our study suggested activation of the TGFβ signaling pathway in the nonresponders
may occur through an autocrine loop. Inhibition of this pathway in the SNUC cell line
successfully showed inhibition of growth and survival under cisplatin. Our study may
offer hope to SNUC patients struggling with chemoresistance.
