Role of COX7RP in Endometrial, Breast Cancer Growth

Researchers in Japan recently investigated the contributions of mitochondrial respiration in tumorigenesis, as these respirations produce ATP and cancerous metabolites that give cancer cells a boost. Their results were reported in Nature Communications.

Endometrial cancer, along with breast cancer, is a commonly known endocrine-related cancer, stimulated by estrogen in both onset and growth of malignancies. Previously identified through genomic binding site cloning was the estrogen-responsive gene, COX7RP/COX7A2L/SCAF1. Although the role of COX7RP is widely known, the exact details of its function remain more ambiguous.

Swift growing tumors provoke greater metabolic demand in order to provide a more efficient energy source for ongoing tumor growth. Although aerobic glycolysis, or the Warburg effect, has long been assumed prototypical culprit in cancer cell growth, more recent research points to mitochondrial respiration as a key player in tumorigenesis. Tumor cells in a number of pathologies have proven reliant on mitochondrial respiration. Then too, metabolic processes such as amino acid and glucose metabolism, lipogenesis, and nucleotide biosynthesis are also to blame for tumor progression. Mitochondrial respiration fosters ATP, and oncogenic metabolites such as2-oxoglutarate and succinate, thus altering epigenetic states of cancer cells. It also produces reactive oxygen species, leading to DNA mutations and tumor growth.

To investigate the clinical relationship between COX7RP in endometrial cancer, as well as in breast cancer, Ikeda, et al. evaluated COX7RP expression in clinical endome-trial cancer samples. The authors reported that COX7RP/COX7A2L/SCAF1, which stabilizes mitochondrial supercomplex assembly, is prolific in breast and endometrial cancer samples. There is a correlation, in fact, between overexpression of COX7RP and cancer prognosis. The authors show that excess COX7RP in endometrial and breast cancer cells increases hypoxia tolerance and exacerbates in vitro and in vivo growth,

The researchers detected substantial COX7RP immunoreactivities in endometrial tumors, but only feeble immunoreactivities were noted in normal glandular epithelial regions. Some of the cancerous tissue had higher COX7RP mRNA levels and the mean levels were quite a bit higher in tumors than they were in normal regions. These observations suggest that COX7RP expression could have clinical significance in estrogen-sensitive endometrial and breast cancers. Additional studies established that COX7RP promotes estrogen-independent tumor growth of MCF7 cells, modulates metabolism, induces respiratory supercomplex assembly, and stimulates oxygen consumption in hypoxia.

The authors discovered that COX7RP overexpression regulates metabolic activities in malignant cells. the effect on steady-state levels of tricarboxylic acid cycle intermediates is especially remarkable. Also significant was that silencing subunits of 2-oxoglutarate dehydrogenase complex appeared to reduce COX7RP-stimulated growth of cancer cells. The authors concluded that in endometrial and breast cancer cells, COX7RP serves as a growth-regulatory factor by modulating metabolic pathways and energy production. In part, this is because COX7RP alters levels of tricarboxylic acid cycle intermediates.