Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

SIMPLE SUMMARY: Targeting the metabolism of cancers is a promising strategy for treatment. In the current study we examine the role of COX4, an enzyme of the mitochondria, in thyroid cancer. The experiments were performed in immortalized cell lines and tissue sample from human thyroid cancers. We examined several types of thyroid cancers, and we found out that the role of COX4 was more pronounced in medullary thyroid cancer. As a result, we believe that COX4 should be studied further as a therapeutic target in medullary thyroid cancer. ABSTRACT: The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC.