The Contribution of PCPH to Colon Carcinoma

Abstract

PCPH is a well conserved, single-copy gene whose product is ubiquitously expressed but predominates in kidney, liver, and colon. The protein product belongs to the nucleoside triphosphate diphosphohydrolase family, NTPDase, but the biological function of PCPH is unknown. The oncogenic potential of PCPH (or NTPDase 5) and mutant-PCPH (mt-PCPH) has been demonstrated in several cell systems. Interestingly, mt-PCPH and PCPH expression consistently altered cellular ATP levels, chemoresistance, and invasive propensity, yet the induction of these phenotypes appeared to be mediated by different signaling pathways depending on the cellular context. In every case, the extent of the effects of mt-PCPH expression was substantially greater than those of PCPH.

It has also been demonstrated that PCPH and mt-PCPH expression levels were altered in cancers compared to normal tissue. The literature shows that PCPH/mt-PCPH mRNA expression levels change in colon tissue with the onset of colorectal cancer. The colon is an organ in which cancer is prevalent and PCPH/mt-PCPH expression has been demonstrated but not well described. This study investigated the relationship between PCPH and mt-PCPH expression and colorectal cancer by immunohistochemical analysis of colon tumors and ectopic expression in colon-derived cells.

Results demonstrated a putative role for mt-PCPH in colorectal cancer invasion using solid tumors and cell culture models. The increased invasiveness upon expression of mt-PCPH was mediated by increased FAK, whose levels were likely elevated through protein-interaction induced FAK stabilization. Results also demonstrated that though PCPH has enzyme activity and shares a significant portion of conserved amino acid sequence with mt-PCPH, mt-PCPH is an enzymatically inactive polypeptide, which possibly confers its effects on cellular ATP levels and cell viability through a novel interaction with the ANT2 protein, a mitochondrial membrane protein responsible for ADP/ATP exchange with the cytosol and a component of the ATP synthasome and the mitochondrial permeability transition pore complex.

Data indicated a potential for the use of mt-PCPH expression to detect invasive or chemoresistant cells in colorectal cancers. Importantly, data demonstrated that the enzymatic activity of mt-PCPH is not necessary for oncogenicity and suggest a universal, enzymatic activity-independent mechanism of oncogenicity significant to this field of research.