Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Sweet, Rebecca; Paul, Amber M.; Zastre, Jason

doi:10.4161/cbt.10.11.13444

Cited by 29 publications

(36 citation statements)

References 37 publications

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“…Moreover, hypoxic stress (e.g. indicated by TKTL1 or LDH5 expression) may increase thiamine uptake by the thiamine transporter SLC19A3 in a tumor cells [57]. Independent of hypoxia, pyruvate accumulation [58] and TKTL1 expression [30] may lead to HIF1-a stabilization.…”

Section: Discussionmentioning

confidence: 99%

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Grimm¹,

Calgéer²,

Teriete

et al. 2015

Clin Transl Oncol

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Section: Discussionmentioning

confidence: 99%

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Grimm¹,

Calgéer²,

Teriete

et al. 2015

Clin Transl Oncol

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show abstract

Section: Reviewmentioning

confidence: 99%

“…demonstrated that hypoxic exposure resulted in upregulation or re-establishment of SLC19A3 expression in breast cancer cells [26]. A corresponding 2-fold increase in thiamine transport was also observed, suggestive of an increased requirement for thiamine during hypoxic stress [26]. The presence of hypoxic microenvironments in tumors results in an increase in glycolytic activity, primarily controlled by the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor.…”

Section: Reviewmentioning

confidence: 99%

“…The presence of hypoxic microenvironments in tumors results in an increase in glycolytic activity, primarily controlled by the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor. Knockdown of HIF-1α attenuated the upregulation, suggesting that SLC19A3 may be an associated gene involved in the adaptive metabolic shift during hypoxic stress [26]. Interestingly, thiamine was shown to reduce hypoxia-mediated apoptosis of rat cardiomyocytes [27].…”

Section: Reviewmentioning

confidence: 99%

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Linking vitamin B1 with cancer cell metabolism

et al. 2013

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The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose and micronutrients functioning as enzyme cofactors is required. The majority of co-enzymes are water-soluble vitamins such as niacin, folic acid, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is underappreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells.

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“…Recently, we have reported on the potential involvement of hypoxia inducible factor-1 alpha (HIF-1α) in adaptively regulating thiamine transport during pathophysiological stress (13, 14). Under hypoxic conditions the expression of SLC19A3 was adaptively up-regulated, while SLC19A2 expression remained unchanged (13).…”

Section: 0 Introductionmentioning

confidence: 99%

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

Zera

Sweet

Zastre

2016

Gene

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Ensuring continuous intracellular supply of thiamine is essential to maintain metabolism. Cellular homeostasis requires the function of the membrane bound thiamine transporters THTR1 and THTR2. In the absence of increased dietary intake of thiamine, varying intracellular levels to meet metabolic demands during pathophysiological stressors, such as hypoxia, requires adaptive regulatory mechanisms to increase thiamine transport capacity. Previous work has established the up-regulation of SLC19A3 (THTR2) gene expression and activity during hypoxic stress through the activity of the hypoxia inducible transcription factor 1 alpha (HIF-1α). However, it is unknown whether HIF-1α acts directly or indirectly to trans-activate expression of SLC19A3. This work utilized the breast cancer cell line BT-474 treated with 1% O2 or a hypoxia chemical mimetic deferoxamine to determine the minimal promoter region of SLC19A3 responsible for hypoxia responsiveness. In silico sequence analysis determined two contiguous hypoxia responsive elements in close proximity to the transcriptional start site of the SLC19A3 gene. Using a HIF-1α transcriptional factor ELISA assay, HIF-1α was capable of binding to a dsDNA construct of the SLC19A3 minimal promoter. Chromatin immunoprecipitation assay established that SP1 was bound to the SLC19A3 minimal promoter region under normoxic conditions. However, HIF-1α binding to the minimal promoter region occurred during hypoxic treatments, while no SP1 binding was observed under these conditions. This work demonstrates the direct binding and activation of SLC19A3 expression by HIF-1α during hypoxic stress, suggesting an important adaptive regulatory role for HIF-1α in maintaining thiamine homeostasis.

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Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

Cited by 29 publications

References 37 publications

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Linking vitamin B1 with cancer cell metabolism

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

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