Selenoproteins and Metastasis

Abstract

Cancer survival is largely impacted by the dissemination of cancer cells from the original tumor site to secondary tissues or organs through metastasis. Targets for anti-metastatic therapies have recently become a focus of research, but progress will require a better understanding of the molecular mechanisms driving metastasis. Selenoproteins play important roles in many of the cellular activities underlying metastasis including cell adhesion, matrix degradation and migration, invasion into the blood and extravasation into secondary tissues, and subsequent proliferation into metastatic tumors along with the angiogenesis required for growth. In this review the roles identified for different selenoproteins in these steps and how they may promote or inhibit metastatic cancers is discussed. These roles include selenoenzyme modulation of redox tone and detoxification of reactive oxygen species, calcium homeostasis and unfolded protein responses regulated by endoplasmic reticulum selenoproteins, and the multiple physiological responses influenced by other selenoproteins.

Understanding Metal Dynamics Between Cancer Cells and Macrophages: Competition or Synergism?

“…On the other hand, Barrett et al, have highlighted a shift toward M2 phenotype stimulated by IFN-γ and LPS (M1) or IL-13 (M2) in bone marrow derived macrophages isolated from Sepp1 +/− mice (124). In agreement with these results, other studies have associated the selenium deficiency to the loss of GPxs and phagocytic activities of macrophages (M1 feature) toward transformed cells (133,145,150).…”

“…Moreover, Solinas et al, have found SELENOP (SEPP1) upregulated 95-fold at the transcript level in macrophages polarized by cancer cells conditioned media (149). Despite the lack of experimental evidence, it is possible to hypothesize that the increased SELENOP in M2 macrophages may offset the loss of SELENOP in cancer cells and support metastasis by supplying it in a paracrine manner (150). On the other hand, Barrett et al, have highlighted a shift toward M2 phenotype stimulated by IFN-γ and LPS (M1) or IL-13 (M2) in bone marrow derived macrophages isolated from Sepp1 +/− mice (124).…”

Selenoproteins in colon cancer

“…Recently, SELENOI has been added as an additional ER-resident selenoprotein [36]. For some of these, a role in the UPR (SELENOF, SELENOK, SELENOS) or regulation of calcium homeostasis (SELENOK, M, N, T) has been suggested (reviewed in [37]). Thus far, it appears as if evidence among ER-resident selenoproteins for a role in cancer is limited to SELENOF and SELENOS, which are described in this section.…”

“…Surprisingly, a combined targeted down-regulation of both SELENOF and TXNRD1 did not reverse cancer phenotypes, hinting to a more complicated interplay between selenoproteins in CRC [78]. Unfortunately, other information regarding TXNRD1’s role in metastasis is limited to tissues outside the intestinal tract (reviewed in [37]), including targeted downregulation of TXNRD1 in mouse lung carcinoma cells that had similarly resulted in the reversal in the morphology and anchorage-independent growth properties [131]. The mitochondrial TXNRD2 also appears to promote cell invasion and migration [115], which was shown in mouse embryonic fibroblasts, where activation of hypoxia-inducible factor-1α signaling failed in the absence of TXNRD2 [122].…”

Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer

“…A potential link to cancer involves the effect of the hypermodified A37 on tRNA [Ser]Sec functionality and, thereby, on selenoprotein synthesis [ 18 ]. Selenium-containing proteins fulfil pleiotropic roles in carcinogenesis, such as the detoxification of reactive oxygen species, the modulation of calcium homeostasis and unfolded protein responses in the endoplasmic reticulum [ 19 , 20 ], and the reduction in selenoprotein expression due to the impairment of isopentenylated tRNAs [ 9 , 21 ]. These findings prompted us to investigate the presence of genetic and epigenetic defects in the A37-modifying enzymes TRIT1 and CDK5RAP1 in human tumors.…”