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Type 3 deiodinase: role in cancer growth, stemness, and metabolism.

Ciavardelli D, Bellomo M, Crescimanno C, Vella V - Front Endocrinol (Lausanne) (2014)

Bottom Line: THs are essential for proper body development and cellular differentiation.Changes in deiodinases expression are anatomically and temporally regulated and influence the downstream TH signaling.The enhanced TH degradation by D3 induces a local hypothyroidism, thus inhibiting THs transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: School of Human and Social Science, University "Kore" of Enna , Enna , Italy ; Center of Excellence on Aging (CeS.I.), University "G. d'Annunzio" of Chieti-Pescara , Chieti , Italy.

ABSTRACT
Deiodinases are selenoenzymes that catalyze thyroid hormones (THs) activation (type 1 and type 2, D1 and D2, respectively) or inactivation (type 3, D3). THs are essential for proper body development and cellular differentiation. Their intra- and extra-cellular concentrations are tightly regulated by deiodinases with a pre-receptorial control thus generating active or inactive form of THs. Changes in deiodinases expression are anatomically and temporally regulated and influence the downstream TH signaling. D3 overexpression is a feature of proliferative tissues such as embryo or cancer tissues. The enhanced TH degradation by D3 induces a local hypothyroidism, thus inhibiting THs transcriptional activity. Of note, overexpression of D3 is a feature of several highly proliferative cancers. In this paper, we review recent advances in the role of D3 in cancer growth, stemness, and metabolic phenotype. In particular, we focus on the main signaling pathways that result in the overexpression of D3 in cancer cells and are known to be relevant to cancer development, progression, and recurrence. We also discuss the potential role of D3 in cancer stem cells metabolic phenotype, an emerging topic in cancer research.

No MeSH data available.


Related in: MedlinePlus

Effects of type 3 deiodinase expression on Warburg phenotype. Hypoxia or oncogenic signals inhibit HIF-1a degradation and stabilize the nuclear association between HIF-1a and HIF-1b resulting in the transactivation of HIF-1 target genes. The activation of the M2 isoform of pyruvate kinase (PKM2), lactate dehydrogenase A (LDHA), and of the pyruvate dehydrogenase kinase 1 (PDHK1) that, in turn, inhibits the mitochondrial pyruvate dehydrogenase (PDH) shunts cell metabolism from the mitochondrial respiration toward the fermentative glycolysis. Furthermore, the induction of max interactor 1 (MXI1), a transcriptional target of HIF-1 complex, inhibits mitochondrial biogenesis through the downexpression of nuclearly encoded mitochondrial genes. The coexpression of type 3 deiodinase (D3) decreases cytosolic triiodothyronine (T3) levels resulting in the activation of PKM2. It is also possible that D3 translocates from cytoplasm to the cell nucleus mediating nuclear thyroid hormone inactivation and local hypothyroidism. Bold arrows indicate activation, whereas the blunted lines indicate inhibition. Dashed arrows indicate protein translocation between cellular compartments. Dotted lines indicate the pathway reactions.
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Figure 1: Effects of type 3 deiodinase expression on Warburg phenotype. Hypoxia or oncogenic signals inhibit HIF-1a degradation and stabilize the nuclear association between HIF-1a and HIF-1b resulting in the transactivation of HIF-1 target genes. The activation of the M2 isoform of pyruvate kinase (PKM2), lactate dehydrogenase A (LDHA), and of the pyruvate dehydrogenase kinase 1 (PDHK1) that, in turn, inhibits the mitochondrial pyruvate dehydrogenase (PDH) shunts cell metabolism from the mitochondrial respiration toward the fermentative glycolysis. Furthermore, the induction of max interactor 1 (MXI1), a transcriptional target of HIF-1 complex, inhibits mitochondrial biogenesis through the downexpression of nuclearly encoded mitochondrial genes. The coexpression of type 3 deiodinase (D3) decreases cytosolic triiodothyronine (T3) levels resulting in the activation of PKM2. It is also possible that D3 translocates from cytoplasm to the cell nucleus mediating nuclear thyroid hormone inactivation and local hypothyroidism. Bold arrows indicate activation, whereas the blunted lines indicate inhibition. Dashed arrows indicate protein translocation between cellular compartments. Dotted lines indicate the pathway reactions.

Mentions: As discussed above, D3 is involved in the adaptative response to hypoxia in cells and is trascriptionally induced by HIF-1α (31) as well as other molecular mediators of the Warburg effect such as hexokinase, pyruvate kinase (PK), and lactate deydrogenase (Figure 1). Notably, the embryonic and low activity isoform of PK, PKM2, is enriched in CSCs and promotes the aerobic glycolysis thus contributing to anabolic metabolism. T3 has been reported as an allosteric inhibitor of PKM2 in vitro (69, 70). Therefore, the overexpression of D3 and the resulting decrease of cytosolic T3 increase PKM2 activity stimulating the aerobic glycolysis (Figure 1). Furthermore, in neurons, hypoxia induces heat-shock protein-40 (Hsp-40)-mediated nuclear import of D3 that facilitate THs inactivation resulting in nuclear hypothyroidism and reducing cellular metabolism and oxygen consumption (71). Although this mechanism has not been yet reported in cancer cells, it is worthy of note that Hsp-40, also known as DNAJB1, and the other members of DNAJ family have been found to be involved in the regulation of cancer cells and CSCs (72). The function of Hsp-40 is still controversial because this chaperone protein may interact with PKM2 inducing its degradation and impairing tumor cell proliferation (73). However, some CSCs isolated from specific solid tumors display increased levels of Hsp-40 (74). Therefore, it is intriguing to speculate that D3 could contribute to the glycolytic phenotype of CSCs and therefore provide an additional target to counteract CSCs metabolism.


Type 3 deiodinase: role in cancer growth, stemness, and metabolism.

Ciavardelli D, Bellomo M, Crescimanno C, Vella V - Front Endocrinol (Lausanne) (2014)

Effects of type 3 deiodinase expression on Warburg phenotype. Hypoxia or oncogenic signals inhibit HIF-1a degradation and stabilize the nuclear association between HIF-1a and HIF-1b resulting in the transactivation of HIF-1 target genes. The activation of the M2 isoform of pyruvate kinase (PKM2), lactate dehydrogenase A (LDHA), and of the pyruvate dehydrogenase kinase 1 (PDHK1) that, in turn, inhibits the mitochondrial pyruvate dehydrogenase (PDH) shunts cell metabolism from the mitochondrial respiration toward the fermentative glycolysis. Furthermore, the induction of max interactor 1 (MXI1), a transcriptional target of HIF-1 complex, inhibits mitochondrial biogenesis through the downexpression of nuclearly encoded mitochondrial genes. The coexpression of type 3 deiodinase (D3) decreases cytosolic triiodothyronine (T3) levels resulting in the activation of PKM2. It is also possible that D3 translocates from cytoplasm to the cell nucleus mediating nuclear thyroid hormone inactivation and local hypothyroidism. Bold arrows indicate activation, whereas the blunted lines indicate inhibition. Dashed arrows indicate protein translocation between cellular compartments. Dotted lines indicate the pathway reactions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269192&req=5

Figure 1: Effects of type 3 deiodinase expression on Warburg phenotype. Hypoxia or oncogenic signals inhibit HIF-1a degradation and stabilize the nuclear association between HIF-1a and HIF-1b resulting in the transactivation of HIF-1 target genes. The activation of the M2 isoform of pyruvate kinase (PKM2), lactate dehydrogenase A (LDHA), and of the pyruvate dehydrogenase kinase 1 (PDHK1) that, in turn, inhibits the mitochondrial pyruvate dehydrogenase (PDH) shunts cell metabolism from the mitochondrial respiration toward the fermentative glycolysis. Furthermore, the induction of max interactor 1 (MXI1), a transcriptional target of HIF-1 complex, inhibits mitochondrial biogenesis through the downexpression of nuclearly encoded mitochondrial genes. The coexpression of type 3 deiodinase (D3) decreases cytosolic triiodothyronine (T3) levels resulting in the activation of PKM2. It is also possible that D3 translocates from cytoplasm to the cell nucleus mediating nuclear thyroid hormone inactivation and local hypothyroidism. Bold arrows indicate activation, whereas the blunted lines indicate inhibition. Dashed arrows indicate protein translocation between cellular compartments. Dotted lines indicate the pathway reactions.
Mentions: As discussed above, D3 is involved in the adaptative response to hypoxia in cells and is trascriptionally induced by HIF-1α (31) as well as other molecular mediators of the Warburg effect such as hexokinase, pyruvate kinase (PK), and lactate deydrogenase (Figure 1). Notably, the embryonic and low activity isoform of PK, PKM2, is enriched in CSCs and promotes the aerobic glycolysis thus contributing to anabolic metabolism. T3 has been reported as an allosteric inhibitor of PKM2 in vitro (69, 70). Therefore, the overexpression of D3 and the resulting decrease of cytosolic T3 increase PKM2 activity stimulating the aerobic glycolysis (Figure 1). Furthermore, in neurons, hypoxia induces heat-shock protein-40 (Hsp-40)-mediated nuclear import of D3 that facilitate THs inactivation resulting in nuclear hypothyroidism and reducing cellular metabolism and oxygen consumption (71). Although this mechanism has not been yet reported in cancer cells, it is worthy of note that Hsp-40, also known as DNAJB1, and the other members of DNAJ family have been found to be involved in the regulation of cancer cells and CSCs (72). The function of Hsp-40 is still controversial because this chaperone protein may interact with PKM2 inducing its degradation and impairing tumor cell proliferation (73). However, some CSCs isolated from specific solid tumors display increased levels of Hsp-40 (74). Therefore, it is intriguing to speculate that D3 could contribute to the glycolytic phenotype of CSCs and therefore provide an additional target to counteract CSCs metabolism.

Bottom Line: THs are essential for proper body development and cellular differentiation.Changes in deiodinases expression are anatomically and temporally regulated and influence the downstream TH signaling.The enhanced TH degradation by D3 induces a local hypothyroidism, thus inhibiting THs transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: School of Human and Social Science, University "Kore" of Enna , Enna , Italy ; Center of Excellence on Aging (CeS.I.), University "G. d'Annunzio" of Chieti-Pescara , Chieti , Italy.

ABSTRACT
Deiodinases are selenoenzymes that catalyze thyroid hormones (THs) activation (type 1 and type 2, D1 and D2, respectively) or inactivation (type 3, D3). THs are essential for proper body development and cellular differentiation. Their intra- and extra-cellular concentrations are tightly regulated by deiodinases with a pre-receptorial control thus generating active or inactive form of THs. Changes in deiodinases expression are anatomically and temporally regulated and influence the downstream TH signaling. D3 overexpression is a feature of proliferative tissues such as embryo or cancer tissues. The enhanced TH degradation by D3 induces a local hypothyroidism, thus inhibiting THs transcriptional activity. Of note, overexpression of D3 is a feature of several highly proliferative cancers. In this paper, we review recent advances in the role of D3 in cancer growth, stemness, and metabolic phenotype. In particular, we focus on the main signaling pathways that result in the overexpression of D3 in cancer cells and are known to be relevant to cancer development, progression, and recurrence. We also discuss the potential role of D3 in cancer stem cells metabolic phenotype, an emerging topic in cancer research.

No MeSH data available.


Related in: MedlinePlus