The genetic heterogeneity in cancer cells has an increased chance in the acquisition of new mutant such as drug-resistant phenotype in cancer cells. The phenotype of drug resistance in cancer cells could be evaluated by the number or function of drug transporters on cell membranes, which would lead to decreased intracellular anti-cancer drugs concentration. Caveolae are flask-shaped invaginations on cell membrane that function in membrane trafficking, endocytosis, and as a compartment where receptors and signaling proteins are concentrated. Caveolin-1 (CAV1) is the principal structural protein of caveolae and closely correlates with multidrug resistance in cancer cells. In a systematic study of the ubiquitin-modified proteome, lysine 176 of CAV1 was identified as a potential post-translational modification site for ubiquitination. In this article, we identified a mutation at lysine 176 to arginine (K176R) on CAV1 would interfere with the biogenesis of caveolae and broke the interaction of CAV1 with P-glycoprotein. Functional assays further revealed that K176R mutant of CAV1 in cancer cells increased the transport activity of P-glycoprotein and decreased the killing ability of anti-cancer drugs in non-small-cell lung cancer cell lines.
Purposes: Transcription factor NF-κB and its activating kinase IκB Kinase β (IKKβ) are critical for inflammation and innate immunity. In our previoius report, MLN120B, an IKKβ inhibitor, would cause neutrophilia in mice but their peripheral blood lymphocyte numbers were not affected. We tried other IKK inhibitors; however, we found that feeding with BMS-345541, a highly selective IKKβ inhibitor, would cause lymphopenia in mice. We explored the possibility of BMS-345541 as a therapeutic agent in depleting lymphocytes. Results: To characterize how BMS-345541 affects lymphocyte homeostatsis, C57BL/6 mice received vehicle, or BMS-345541 oral gavage once daily at different dose (10, 25, 50, and 100 mg/kg body weight in 3% Tween 80), and mice were sacrificed on day 3 or day 5. We collected the peripheral blood for blood cell counts and also collected spleen and lymphnodes for histology examination. The lymphocytes, but not neutrophils, were significantly decreased in mice received BMS-345541. Our preliminary results showed that the effect of BMS-345541 on lymphocytes were through apoptosis rather than trapping the lymphocytes in lymphoid organs. BMS-345541 affected both T cells and B cells. Conclusion: We conclude that oral administration of BMS-345541 would reduce lymphocyte counts and could be helpful in depleting lymphocytes in circulation, which would be useful as a therapeutic agent for lymphoproliferative disorder.
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