The adaptive regulation of thiamine pyrophosphokinase-1 facilitates malignant growth during supplemental thiamine conditions

Abstract

Supplemental levels of vitamin B1 (thiamine) have been implicated in tumor progression. Tumor cells adaptively up-regulate thiamine transport during hypoxic stress. Upon uptake, thiamine pyrophosphokinase-1 (TPK1) facilitates the rapid phosphorylation of thiamine into thiamine pyrophosphate (TPP). However, the regulation of TPK1 during hypoxic stress is undefined. Understanding how thiamine homeostasis changes during hypoxia will provide critical insight into the malignant advantage supplemental thiamine may provide cancer cells. Using Western blot analysis and RT-PCR, we have demonstrated the post-transcriptional up-regulation of TPK1 in cancer cells following hypoxic exposure. TPK1 expression was also adaptively up-regulated following alterations of redox status by chemotherapeutic and antioxidant treatments. Although TPK1 was functionally up-regulated by hypoxia, HPLC analysis revealed a reduction in intracellular TPP levels. This loss was reversed by treatment with cell-permeable antioxidants and corresponded with reduced ROS production and enhanced cellular proliferation during supplemental thiamine conditions. siRNA-mediated knockdown of TPK1 directly enhanced basal ROS levels and reduced tumor cell proliferation. These findings suggest that the adaptive regulation of TPK1 may be an essential component in the cellular response to oxidative stress, and that during supplemental thiamine conditions its expression may be exploited by tumor cells for a redox advantage contributing to tumor progression.

Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate

“…The major intracellular derivative of thiamine, ThDP, has been added instead of thiamine in view of ThDP involvement in regulation of p53 transcriptional activity ( McLure et al, 2004 ). Given published evidence on transport of ThDP by cellular membrane transporters SLC19A1 ( Zhao et al, 2001 ; Zhao and Goldman, 2013 ) and SLC44A4 ( Nabokina et al, 2014 ), this experimental design may overcome complex regulation of ThDP synthesis in cancer cells ( Jonus et al, 2018 ), being more straightforward to extend the interval of intracellular ThDP content. Expression of SLC19A1 is documented in A549 cells ( Kawami et al, 2015 ), as is the expression of choline transporters-like CTL/SLC44 proteins ( Inazu, 2014 ) sharing the same family with the ThDP-transporting SLC44A4.…”

Dibenzoylthiamine Has Powerful Antioxidant and Anti-Inflammatory Properties in Cultured Cells and in Mouse Models of Stress and Neurodegeneration

“…As already suggested for BFT, the coenzyme ThDP does not seem to be involved: we showed that in the presence of pyrithiamine, no net ThDP synthesis occurred during incubation with DBT, but its protective effects were maintained both in Neuro2a and BV2 cells ( Figure 13 ). It was recently suggested that ThDP could have an antioxidant effect that is independent of its coenzyme role [ 55 ]. DBT was no more efficient in raising intracellular ThDP concentrations than thiamine, SuBT, or BFT in Neuro2a ( Supplemental Figure S2 ) and BV2 cells ( Supplemental Figure S12 ), though it was pharmacologically more active.…”

B Vitamins and Their Role in Immune Regulation and Cancer

“…Despite the upregulation of TPK1, intracellular TPP was decreased. SiRNA knockdown of TPK1 reduced tumor cell proliferation, suggesting that increased TPP supports increased tumor growth [20]. A study motivated by the observation of poor thiamine bioavailability in tumors developed thiamine mimetics to improve delivery to cells.…”