What is Metallothionein?
Metallothionein are low-molecular-weight cysteine-based proteins that trap metal ions with thiol groups. MT was first identified in 1957 by Margoshes and Vallee and is a metalloprotein, because of its abundance of metals and unusual bioinorganic architecture. These proteins are ubiquitous in eukaryotes and are most frequently involved in metal ion homeostasis, detoxification and antioxidation. MT also has the characteristic high cysteine ratio (roughly 30%) and lack of aromatic amino acids for highly selective interactions with zinc, copper, cadmium and mercury.
Fig.1 The spatial structure of metallothionein. General structure of MTs: a dumbell-like shape with two separate globular domains α and β[1].
What is the Function of the Metallothionein?
Metal Ion Regulation
MT is involved in the intracellular homeostasis of these critical metals: zinc, copper and so on. It allows for dynamic exchange and storage of metal, which ensures that the cells run properly. Its capacity to scavenge metal ions helps to guard cells from heavy metal toxicity.
Antioxidant Activity
High cysteine content makes MT extremely antioxidant. In neutralizing hydroxyl radicals, it works as an antioxidant against oxidative stress. This is especially important for quickly dividing tissues and during radiation treatment, where MT helps protect cells from free radical-mediated damage.
Cytoprotection
Since MT is strongly bound to divalent heavy metal ions, it can be used to detoxify cadmium, mercury, platinum and other harmful metals, protecting cells and tissues from the harmful elements. MT also alters apoptotic processes and acts anti-apoptotic under stress, such as in the case of anticancer medications.
Neurological Functions
Some isoforms, like MT-3, are mainly present in the central nervous system. MT-3 is neuroprotective in Alzheimer's and Parkinson's disease and an inhibitor of neural growth during development.
Fig.2 Metallothionein redox cycle[2].
What is an Example of a Metallothionein?
Humans have four microtubule isoforms, the MT1, MT2, MT3 and MT4, each with their own distribution and role. Of these four isoforms, MT1 and MT2 are widely expressed in many tissues, while MT3 and MT4 are smaller isoforms with narrow distribution in special cells and tissues (e.g., brain, reproductive tract, complex squamous epithelium).
| Isoform | Expression | Primary Locations | Key Functions |
| MT-1 | Ubiquitous | Liver, kidney, astrocytes | Metal detoxification, zinc and copper homeostasis |
| MT-2 | Ubiquitous | Liver, kidney, astrocytes | Similar to MT-1 |
| MT-3 | Restricted | Neurons, astrocytes | Neuroprotection, growth inhibition |
| MT-4 | Specific | Skin, squamous epithelia | Epithelial protection, pH regulation |
Role of Metallothionein in Cancer
MT expression is significantly elevated in a variety of cancers and is closely associated with cancer onset, progression, and drug resistance.
Encourage proliferation and migration of cancer cells
We found that MT is both pro- and anti-apoptotic in various cancer cells. MT shields cancer cells from oxidative damage by clearing the pathogen's reactive oxygen species (ROS) and keeping the cell balanced. Moreover, MT can also facilitate cancer cell invasion and migration through modulating signaling pathways (e.g., PI3K/Akt, NF-B) that drive tumor growth.
Relationship with chemotherapy resistance
Expressed MT is strongly correlated with resistance to many anticancer agents (cisplatin, adriamycin). MT inhibits cytotoxicity either directly via binding to drug molecules or via counteracting chemotherapy-induced oxidative stress. This is a side-effect that makes cancer cells more resistant to standard chemotherapies.
As a diagnostic and prognostic marker
Since MT is abundantly expressed in cancer tissues much more than in healthy tissues, it has been investigated extensively as a cancer diagnostic and prognostic marker. In breast and ovarian cancer, for instance, overexpression of MT is generally associated with poor outcomes. Moreover, MT expression can be used to predict the sensitivity of a patient to chemotherapy.
Tumor angiogenesis
There are a few studies that have implicated MT in tumor angiogenesis. MT1 is expressed in EC near angiogenesis, and de-expressing MT1 in EC prevents cell proliferation, migration and angiogenesis in vitro, so MT1 is a player in angiogenesis regulation.
VEGF is a critical regulator of angiogenic mechanisms (EC expansion, migration and germination). They have found that MT3 can essentially induce VEGF expression in brain EC via an HIF-1-dependent pathway and that MT2 regulates EC proliferation, migration and angiogenesis in front of VEGF.
Fig.3 Roles of MTs in tumor angiogenesis. ECM, extracellular matrix; ECs, endothelial cells; SMCs, smooth muscle cells[3].
Matrix metallopeptidase (MMP)-9 (gelatinase B) has long been a key regulator of tumour development as it is involved in ECM remodeling, angiogenesis and neointima formation MMP-9 is part of the zinc-dependent metalloproteinases and has been found to act on MT. The idea, then, is that MT is angiogenetic through MMP-9. MTs can also trigger upregulation of angiogenesis genes (e.g., VEGF, MMP-9), which interact with ECs, SMCs and macrophages to form neointima, increasing tumor size, spread and metastasis. And thus future research on MTs could offer targets to inhibit angiogenesis and tumour growth.
Potential therapeutic targets
Stopping MT activity would be expected to improve the performance of chemotherapy drugs. Some have even looked at knocking down MT expression with RNA interference or small molecule inhibitors in order to improve the responsiveness of cancer cells to therapy.
Conclusion
Metallothionein is an example of a protein family with many biological functions, such as metal detoxification, antioxidant activity, and cellular defence. Its isoform-specificity and inducible expression indicate that it maintains cellular integrity under physiological and pathological conditions. and pathological conditions. It plays multifaceted roles in cancer, in tumor formation and growth, and in the regulation of treatment effectiveness. The next round of detailed research on the regulatory biology of MT will offer novel approaches to cancer diagnosis and therapy.
References
- Yang Z., et al. Towards Understanding Plant Response to Heavy Metal Stress. In book: Abiotic Stress in Plants - Mechanisms and Adaptations (2011).
- Jamrozik D., et al. Metallothioneins, a Part of the Retinal Endogenous Protective System in Various Ocular Diseases. Antioxidants (2023).
- Si M., et al. The roles of metallothioneins in carcinogenesis. Journal of Hematology & Oncology (2018).
