P-251 - Smad4 loss is associated with decreased oxidative metabolism in pancreatic cancer and affects sensitivity to mitochondrial therapy

Abstract

Pancreatic cancer is one of the most challenging types of tumors to treat. This is likely caused by a population of resistant cancer cells (CS), which are reported to rely on functional mitochondria. We have shown that mitochondrial targeting is an efficient way to eliminate CS. At the same time, we believe that loss of Smad4, a mediator of transforming growth factor 3 (TGF3) pathway, might be the cause of metabolic reprogramming resulting in mitochondrial dysfunction of pancreatic cancer cells (PCC). We demonstrated that respiration of Smad4+ PCC was substantially decreased when TGF3 was applied. By contrast, Smad4-/- PCC as well as Smad4 knocked out (KO) cells showed lower basal respiration level and they were insensitive to TGF3 treatment. Furthermore, we observed significant changes in mitochondrial fragmentation of Smad4+ PCC after TGF3 treatment, while Smad4 KO PCC remained unaffected. Finally, the Smad4 expression profile correlated with the vulnerability of PCC to mitochondrial-targeted inhibitor of complex I, MitoMet. Our results suggest that loss of Smad4 leads to metabolic reprogramming of PCC, which consequently impacts the sensitivity to mitochondrial-targeted therapy. Based on these findings, we propose a new treatment approach aimed at efficient elimination of PCC.