CA19-9 (carbohydrate antigen 19-9, also called cancer antigen 19-9 or sialylated Lewis a antigen) is the most commonly used and best validated serum tumor marker for pancreatic cancer diagnosis in symptomatic patients and for monitoring therapy in patients with pancreatic adenocarcinoma. Normally synthesized by normal human pancreatic and biliary ductal cells and by gastric, colon, endometrial and salivary epithelia, CA 19-9 is present in small amounts in serum, and can be over expressed in several benign gastrointestinal disorders. Importantly, it exhibits a dramatic increase in its plasmatic levels during neoplastic disease. However, several critical aspects for its clinical use, such as false negative results in subjects with Lewis (a-b-) genotype and false positive elevation, occasional and transient, in patients with benign diseases, together with its poor positive predictive value (72.3 %), do not make it a good cancer-specific marker and renders it impotent as a screening tool. In the last years a large number of putative biomarkers for pancreatic cancer have been proposed, most of which is lacking of large scale validation. In addition, none of these has showed to possess the requisite sensitivity/specificity to be introduced in clinical use. Therefore, although with important limitations we well-know, CA 19-9 continues being the only pancreatic cancer marker actually in clinical use.
Mitochondrial dysfunction and mutations in mitochondrial DNA have been implicated in a wide variety of human diseases, including cancer. In recent years, considerable advances in genomic, proteomic and bioinformatic technologies have made it possible the analysis of mitochondrial proteome, leading to the identification of over 1,000 proteins which have been assigned unambiguously to mitochondria. Defining the mitochondrial proteome is a fundamental step for fully understanding the organelle functions as well as mechanisms underlying mitochondrial pathology. In fact, besides giving information on mitochondrial physiology, by characterizing all the components of this subcellular organelle, the application of proteomic technologies permitted now to study the proteins involved in many crucial properties in cell signaling, cell differentiation and cell death and, in particular, to identify mitochondrial proteins that are aberrantly expressed in cancer cells. An improved understanding of the mitochondrial proteome could be essential to shed light on the connection between mitochondrial dysfunction, deregulation of apoptosis and tumorigenesis and to discovery new therapeutic targets for mitochondria-related diseases.
Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.
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