[Cysteine cathepsins: structure, physiological functions and their role in carcinogenesis].

Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases (EC 3.4.22). Cts are known as lysosomal proteases responsible for the intracellular proteins degradation. All Cts are synthesized as zymogens, activation of which occurs autocatalytically. Their activity is regulated by endogenous inhibitors. Cts can be secreted into the extracellular environment, which is of particular importance in tumor progression. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling, processing and/or release of cell adhesion molecules, growth factors, cytokines and chemokines. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space, which correlates with neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, therefore, their role in the tumor development differs depending on their cellular origin. The mechanism of Cts action in cancer is not limited only by their proteolytic action. The Cts influence on signal transduction pathways associated with cancer development, including the pathway involving growth factors, which is mediated through receptors tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), has been proven. In addition, Cts are able to promote the epithelial-mesenchymal transition (EMT) by activating signal transduction pathways such as Wnt, Notch, and the pathway involving TGF-β. So, Ctc perform specific both destructive and regulatory functions, carrying out proteolysis, both inside and outside the cell.Tsisteinovye katepsiny (Tsk) otnosiatsia k samomu mnogochislennomu semeĭstvu tsisteinovykh proteinaz. Bol'shinstvo Tsk iavliaiutsia éndopeptidazami, nekotorye iz nikh obladaiut ékzopeptidaznoĭ aktivnost'iu. Vse Tsk sinteziruiutsia v vide zimogenov, aktivatsiia bol'shinstva iz nikh proiskhodit avtokataliticheski. Aktivnost' Tsk zavisit ot rN i reguliruetsia éndogennymi ingibitorami. Khotia osnovnaia funktsiia Tsk zakliuchaetsia v rasshcheplenii vnutrikletochnykh belkov v lizosomakh, éti fermenty obnaruzhivaiutsia takzhe v iadre, tsitoplazme, plazmaticheskoĭ membrane i vo vnekletochnoĭ srede. Poslednee imeet osoboe znachenie pri razlichnykh patologicheskikh protsessakh, vkliuchaia rak. Vnekletochnye Tsk ne tol'ko gidrolizuiut belki vnekletochnogo matriksa (VKM), no takzhe vnosiat vklad v reguliatsiiu i rekonstruirovanie VKM posredstvom spetsificheskogo protsessinga riada belkov, vkliuchaia tsitokiny, khemokiny, adgezivnye belki. V norme ékspressiia i aktivnost' Tsk ochen' neznachitel'ny i obnaruzhivaiutsia v osnovnom vnutri kletki. Pri rake ékspressiia i aktivnost' Tsk rezko vozrastaiut kak v kletochnykh lizosomakh, tak i v mezhkletochnom prostranstve, chto sposobstvuet neoplasticheskoĭ transformatsii i privodit k opukholevomu rostu, invazii i dal'neĭshemu progressirovaniiu opukholevogo protsessa. Pokazano, chto velichina ékspressii Tsk zavisit ot tipa kletok, poétomu rol' Tsk v razvitii opukholeĭ razlichaetsia v zavisimosti ot ikh kletochnogo proiskhozhdeniia. Odnako mekhanizm deĭstviia Tsk sviazan ne tol'ko s proteoliticheskoĭ degradatsieĭ belkov VKM, no takzhe s ikh rol'iu v protsessinge belkov, vovlechennykh v onkogennyĭ kletochnyĭ signaling. Tak, uchastie Tsk v protsessinge faktorov rosta oposreduetsia cherez retseptornye tirozinkinazy (RTK) i razlichnye signal'nye mitogen-aktiviruemye proteinkinazy (MAPK), kotorye uchastvuiut v reguliatsii takikh kletochnykh protsessov, kak transkriptsiia genov, apoptoz, proliferatsiia i sposobnost' k migratsii. Krome togo, Tsk sposobstvuiut épitelial'no-mezenkhimal'nomu perekhodu (ÉMP) posredstvom vliianiia na TGF-β-signaling, kotoryĭ rassmatrivaetsia v kachestve odnogo iz kliuchevykh signal'nykh puteĭ v étom protsesse.