The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumour survival

Abstract

Metallothionein is a multi-functional protein that protects the host against toxic heavy metals. Under stressful situations it can protect against oxidative damage, contribute to tissue repair, modulate immune responses and limit inflammatory processes. Recently, metallothionein's role in ultraviolet radiation (UVR)-induced injury has been investigated. These studies have shown that when metallothionein is upregulated following exposure to UVR, it can protect against UVR-induced damage and the subsequent development of skin cancer. We propose that this initial protection is achieved through its anti-oxidant role resulting in reduced oxidative stress, reduced apoptosis, reduced NFkappaB activation and enhanced repair of DNA damage. However, once UVR-induced neoplasia has occurred, the cancer cells can hijack metallothionein's protective functions, resulting in increased tumour progression and malignancy. These two discordant sets of attributes are context-dependent, and represent the two faces of metallothionein.

Overview of the molecular defense systems used by sea urchin embryos to cope with UV radiation

“…The Pl-14-3-3 epsilon mRNA levels increased at both 2 and 24hpi for the two UVB doses used (0.4 and 0.8 kJ/m 2 ), while the mRNA levels of Pl-MT, a metal detoxification and stress gene, increased only with the dose of 0.8 kJ/m 2 at 24hpi. This result agrees with the MT's protective role against ionizing radiation previously observed in mammalian cells (McGee et al, 2010). Three transcription factors, Pl-NF-kB, Pl-jun and Pl-FOXO have been also analyzed.…”

“…One of the possibilities is an enhanced production of ROS, as suggested by Steevens et al (1999) for the co-exposure of L. variegatus embryos to PAHs/UVB, and that might similarly occur in P. lividus embryos after Cd/UVB exposure. Moreover, the increased Pl-MT mRNA levels support this possibility, in agreement with the MT role as radicalscavenger and/or its ROS-quenching activity (McGee et al, 2010).…”

Metallothioneins and zinc in cancer diagnosis and therapy

“…The regulatory power of the redox environment lies in its capacity to control growth behavior, spread, and differentiation (McGee et al, 2010;Cai et al, 1999;Sato and Bremner, 1993). Neoplastic cells adapt to a wide variety of environmental conditions, including persistent OS and genomic instability, by shifting their redox environment to more-reductive conditions, which, in turn, triggers the upregulation of various redox-sensitive prosurvival pathways, including MT transcription and translation (Ostrakhovitch, 2011).…”

Expression of metallothionein I/II and Ki-67 antigen in various histological types of basal cell carcinoma

“…Moreover, a decline of MT-I/II expression is associated with a decrease of PCNA and Ki-67 expression both in sun-exposed and sun-protected skin, which may indicate its impact on cell proliferation [18]. It has been suggested that MT-I/II may protect skin tissues from ultraviolet radiation (UVR) induced carcinogenesis on the one hand, but may induce tumor growth once these occur [19].…”