br STAR Methods br Author Contributions br Acknowledgments T
Acknowledgments The authors thank Monika Kuhn for excellent technical assistance and Dr. Antje Schäfer for valuable scientific input. H.S. was supported by the DFG (FZ 82; Graduate School of Life Sciences and SCHI 425-6/1), and A.V.S. by Northwestern University and the Pew Charitable Trusts as Pew Scholar in the Biomedical Sciences. We thank Dr. Titia Sixma and Dr. Sonja Lorenz for kindly providing the plasmid constructs for human UBA1 and ubiquitin, respectively. We also thank BESSY and ESRF for synchrotron beamtime and support.
Acknowledgement The authors thank the for funding this research.
Introduction Abnormal enzyme activation is a pivotal reason of pathologies, which include allergies, auto-immune diseases, neuropathologies, and cancers (Wong et al., 2009, Wang et al., 2015). The zymogen forms of enzymes are converted to their active forms by different stressors. Such stressors can be the reactive oxygen species (ROS), reactive nitrogen species (RNS) etc. Due to the hyper-production of these reactive free radicals, the extracellular physiological milieu turns acidic (Rajamäki et al., 2013). The resultant low pH favors the activation of a number of crucial enzymes, often triggering ‘enzyme cascades’. A number of studies have reported the direct nexus between high acidic environment, hypoxia and tumorigenesis (Cao et al., 2015). Also, low pH mediating drug resistance has got adequate evidence (Wojtkowiak et al., 2011, Pellegrini et al., 2014). Insightful reviews have critically analyzed these aspects (McCarty and Whitaker, 2010, Kato et al., 2013, Peppicelli et al., 2014). Extracellular acidity is linked to sphingosine kinase inhibitor hypoxia-ischemia as well (McDonald et al., 1998). The acidosis activates acid-sensing ion channels (proton-gated sodium channels), leading to pain and anxiety (Wemmie et al., 2013, Li and Xu, 2015, Li et al., 2016). Also, the dropped pH in the extracellular space leaches calcium from osteoclasts, leading to bone pathologies as osteoporosis and osteomalacia (Jehle and Krapf; Teti et al., 1989). Dietary acid load has been attributed to chronic kidney disease (CKD) (Scialla and Anderson, 2013). Also, depletion of muscle mass as causal of acidosis has been observed, which occurs by activated ubiquitin–proteasome system (UPS) (Jehle and Krapf, 2010; Rajan and Mitch, 2008). A range of metabolic pathologies as diabetic ketosis, trauma, sepsis, chronic obstructive pulmonary disease (COPD), brain ailments etc. have been linked to acidosis (Schwalfenberg, 2012). In this regard, this review discusses the adverse effects and mechanisms of chronic metabolic acidosis in the form of carcinogenic enzyme activation.
Tumorigenesis and metastasis mechanisms Multiple metabolic pathways operate in the human body. Glycolysis, the anaerobic mechanism of glucose metabolism is predominant in tumor cells, which generates lactate (known as Warburg effect) (Dhup et al., 2012, Kato et al., 2013). Pentose phosphate pathway (PPP) produce high CO2, which ultimately break down by carbonic anhydrase to form H+ and HCO3– (Jiang et al., 2014). A broad array of pumps/transporters play active role in this ionic disturbance. Some well-characterized pumps include the lactate transporter, monocarboxylate transporter, H+-ATPase, Na+/H+ exchanger etc. (Kato et al., 2013). These fluctuations in pH have far-flung consequences in the body. Tumors acquire metastatic property by angiogenesis and cell invasiveness. Cell-cell junctions shattered through Src activation via protein kinase C (PKCα) pathway facilitate the invasion. Proangiogenic growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1R), epidermal growth factor (EGF), and cytokines as IL-8 also promote it (Rofstad et al., 2006, Chen and Sharon, 2013). Lactic acid as an inducer of tumor angiogenesis has been discovered (Dhup et al., 2012).