TIMP-1 Dependent Modulation of Metabolic Profiles Impacts Chemoresistance in NSCLC.

ABSTRACT

The development of chemoresistance remains a significant barrier to treating NSCLC. Alteration of cancer cell metabolism is an important mechanism for chemoresistance. This study explored the role of aberrant metabolism in TIMP-1-mediated chemoresistance. Bioinformatics analysis identified an association of high TIMP-1 with altered energy metabolism. We have defined the role of depolarized mitochondria through a reduction in lactate secretion, higher ROS levels in TIMP-1 KD cells and reduced GSH levels. TIMP-1 modulates the metabolic profile via acetylation of mitochondrial STAT3 and its interaction with CD44. Intriguingly, monomers of acetylated STAT3 were critical for altered metabolism, whereas STAT3 dimers abrogated this function. Further, the mitochondrial metabolic profile was also altered in a cisplatin-resistant clone of A549 cells. We also correlated the immunoexpression of CD44, STAT3 and TIMP-1 in patient samples. This study provided evidence that TIMP-1 alters the metabolic profile by modulating mitochondrial metabolism via the CD44-STAT3 axis through its effects on STAT3 acetylation. It also lent further support to the critical role of TIMP-1 in chemoresistance. Interrogation of the TCGA-LUAD dataset revealed perturbations in the critical modulator that can alter metabolic states in cancer cells. Higher expression of a five-gene signature, including TIMP-1, correlated with immunosuppressive cells and was found to be associated with overall survival. This study identified several metabolic mechanisms that could influence therapeutic options and prognosis in NSCLC patients.