Lyn regulates creatine uptake in an imatinib-resistant CML cell line

Okumu, Denis; Aponte‐Collazo, Lucas J.; Dewar, Brian; Cox, Nathan J.; East, Michael P.; Tech, Katherine; McDonald, Ian M.; Tikunov, Andrey P.; Holmuhamedov, Ekhson; Macdonald, Jeffrey M.; Graves, Lee M.

doi:10.1016/j.bbagen.2019.129507

Cited by 5 publications

(4 citation statements)

References 56 publications

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“…Furthermore, the knowledge of Srckinase activity modulating OATP1B3 activity adds to previous reports of Src kinases regulating activity of other solute carriers, including OATP1B1 and organic cation transporter 2 (Sprowl et al, 2016). LYN was also recently shown to regulate the Na1/K1-ATPase pump (Okumu et al, 2020). Therefore, the current study collectively lends support to the role of Src kinases as regulators of endogenous and xenobiotic uptake or disposition which should be further investigated in vivo and in clinical studies.…”

Section: Discussionsupporting

confidence: 74%

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

et al. 2022

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The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drugdrug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENTThe organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

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Section: Discussionsupporting

confidence: 74%

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

et al. 2022

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“…Electrogenic Na + - and Cl − -dependent Cr transport, with high affinity for Cr (K m ~30 µM), allows IEC to import Cr ingested with the diet (eg, from protein sources such as fish or meat) as the most significant sources for Cr [ 54 ] . As CrT1 function is dependent on Na + , inhibition of the Na + /Ka + -ATPase (eg, through the action of Lyn kinase activation), also inhibits Cr uptake into cells, as shown recently [ 55 ] .…”

Section: Deficiencies Of Creatine Metabolism and Transport In Ibdmentioning

confidence: 91%

Revisiting the “starved gut” hypothesis in inflammatory bowel disease

et al. 2023

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Active episodes of inflammatory bowel disease (IBD), which include ulcerative colitis and Crohn’s disease, coincide with profound shifts in the composition of the microbiota and host metabolic energy demand. Intestinal epithelial cells (IEC) that line the small intestine and colon serve as an initial point for contact for the microbiota and play a central role in innate immunity. In the 1980s, Roediger et al proposed the hypothesis that IBD represented a disease of diminished mucosal nutrition and energy deficiency (“starved gut”) that strongly coincided with the degree of inflammation. These studies informed the scientific community about the important contribution of microbial-derived metabolites, particularly short-chain fatty acids (SCFA) such as butyrate, to overall energy homeostasis. Decades later, it is appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places inordinate demands on energy acquisition within the mucosa, particularly during active inflammation. Here, we review the topic of tissue energetics in mucosal health and disease from the original perspective of that proposed by the starved gut hypothesis.

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“…By this electrogenic Na + - and Cl − -dependent Cr-cotransporter (CrT1), with a high affinity for Cr (Km for Cr of 30 µM), epithelial cells of the intestine take up Cr ingested with the diet, e.g., from meat and fish, as the most significant alimentary sources for Cr [ 12 ]. As CrT1 function is dependent on Na + , inhibition of the Na + /Ka + -ATPase, e.g., by the action of Lyn kinase, also inhibits Cr uptake into cells, as shown recently [ 13 ].…”

Section: Introductionmentioning

confidence: 81%

Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial

Wallimann

Hall

Colgan³

et al. 2021

Nutrients

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Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that “oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn’s disease”. A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3–5 g of Cr per day for a time of 3–6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn’s disease.

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Lyn regulates creatine uptake in an imatinib-resistant CML cell line

Cited by 5 publications

References 56 publications

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

Revisiting the “starved gut” hypothesis in inflammatory bowel disease

Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial

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