Metallothionein isoforms as double agents – Their roles in carcinogenesis, cancer progression and chemoresistance

Abstract

Metallothioneins (MTs) are small cysteine-rich intracellular proteins with four major isoforms identified in mammals, designated MT-1 through MT-4. The best-known biological functions of MTs are their ability to bind and sequester metal ions and their active role in redox homeostasis. Despite these protective roles, numerous studies have demonstrated that changes in MT expression could be associated with the process of carcinogenesis and participation in cell differentiation, proliferation, migration, and angiogenesis. Hence, MTs have the role of double agents, i.e., working with and against cancer. In view of their rich biochemical properties, it is not surprising that MTs participate in the emergence of chemoresistance in tumor cells. Many studies have demonstrated that MT overexpression is involved in the acquisition of resistance to anticancer drugs, including cisplatin, anthracyclines, tyrosine kinase inhibitors and mitomycin. The evidence is slowly becoming available for a cellular switch in MT functions, showing that they indeed have two faces: protector and saboteur.Initially, MTs display anti-oncogenic and protective roles; however, once the oncogenetic process has started, MTs are utilized by cancer cells for progression, survival, and the coordination of chemoresistance. The duality of MTs can serve as a potential prognostic/diagnostic biomarker and can therefore open the door to new strategies in cancer treatment. Herein, we review and discuss MTs as tumor disease markers and describe their role in chemoresistance to distinct anticancer drugs.

Metallothioneins and Megalin Expression Profiling in Premalignant and Malignant Oral Squamous Epithelial Lesions

“…Metallothioneins (MTs) are a phylogenetically conserved family of low molecular weight (6–7 kDa) single-chained and cysteine-rich proteins [ 1 , 2 , 3 ]. In humans, there are four major isoforms of MTs, encoded by clustered genes at chromosome 16q12-22 and identified as MT-I to MT-IV [ 1 ].…”

“…Metallothioneins (MTs) are a phylogenetically conserved family of low molecular weight (6–7 kDa) single-chained and cysteine-rich proteins [ 1 , 2 , 3 ]. In humans, there are four major isoforms of MTs, encoded by clustered genes at chromosome 16q12-22 and identified as MT-I to MT-IV [ 1 ]. MT-I and MT-II show a high degree of sequence matching and are commonly co-regulated, being considered as one functional unit denoted as MT I/II and usually referred as MTs in the narrow sense [ 2 ].…”

“…Owing to these effects, MTs are implicated in the regulation of basic cellular processes, such as cellular growth, differentiation, proliferation, and apoptosis [ 4 , 12 ]. Increased MTs expression has been found to favor cell survival and multiplication, whereby suppresses apoptotic processes, either by directly modulating zinc-dependent transcription factors such as p53 and nuclear factor κB (NFκB) or by protecting DNA from oxidative damage [ 1 , 3 , 13 , 14 , 15 , 16 , 17 , 18 ]. Exerting such cytoprotective and genoprotective activities, MTs ordinarily translocate from cytoplasm to the cellular nucleus [ 19 , 20 ].…”

Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition

“…In the last decade, it has been shown that MTs overexpression is associated with chemoresistance and poor prognosis in a variety of cancers [ 2 ]. Recently, several studies found that resistance to apoptogenic agents is common in cancers that overexpress MTs [ 78 , 79 ].…”

“…Many factors are known to influence the development of secondary resistance, such as the genetic changes of cancer cells, the rate of tumor growth, but also the effects of the microenvironment, e.g., hypoxia which is well known to induce chemo- and radio-resistance [ 2 ]. In the last decades, mechanisms of resistance are intensively investigated, the most well-known ones being: (i) increased drug efflux from the cancer cells or decreased drug entrance to the cancer cells; (ii) downregulation, overexpression, or modification of target molecule(s); (iii) changes in drug activating and ⁄or detoxifying enzymes; (iv) the induction of anti-apoptotic mechanisms or the inactivation of pro-apoptotic mechanisms; (v) decreased access of drug to the target cellular compartments (usually nucleus); (vi) alteration of the cell cycle (most cells move to the G 0 phase when sensitivity to the majority of cytostatics is low); (vii) pharmacological and physiological factors, such as changes in drug metabolism and excretion, and inadequate access of the drug to the tumor including blood brain barrier in brain tumors; and (viii) also microenvironment plays a role in chemoresistance by the production of stimulating factors that induce survival pathways and it also may inactivate drugs [ 1 , 2 , 3 , 4 ]. In addition, a number of studies have revealed the importance of metallothioneins (MT) for the defense mechanisms of tumor cells against the effect of chemotherapy by preventing apoptosis [ 2 ].…”