Abstract
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.
Highlights
The plasma membrane of cells consists of a uniform phospholipid bilayer and of a dynamic assembly of a variety of different lipids and proteins, including small (10–200 nm) sphingolipid- and cholesterol-enriched components termed “lipid rafts”[1]
The formation of CAV1 oligomers was again significantly decreased both in NCI-H460 and A549 cells that were transduced with the CAV1 K176R mutant (Fig. 1b,c) Lipopolysaccharide (LPS) treatment of macrophages has been reported to induce the expression of CAV1 and enhance the formation of CAV1 oligomers[15,16]
We found that the formation of CAV1 oligomers after LPS treatment significantly decreased in RAW264.7 cells that were transduced with the CAV1 K176R mutant (Fig. 1d)
Summary
The plasma membrane of cells consists of a uniform phospholipid bilayer and of a dynamic assembly of a variety of different lipids and proteins, including small (10–200 nm) sphingolipid- and cholesterol-enriched components termed “lipid rafts”[1]. After exposure to an anti-cancer drug, cancer cells can become simultaneously insensitive to unrelated drugs This phenomenon is called multidrug resistance (MDR). P-glycoprotein is reportedly located in lipid rafts and associated with CAV111,12, the influence of the interaction between CAV1 and P-glycoprotein on the development and progression of MDR in cancer cells is largely unknown. We found that the post-translational modification site of CAV1 at lysine 176 influenced the formation of CAV1 oligomers and the interaction between CAV1 and P-glycoprotein, which affected the transport activity of P-glycoprotein in non-small-cell lung cancer cell lines. Our results suggest that the post-translational modification site of CAV1 at lysine 176 influences the drug transport activity of P-glycoprotein and the drug sensitivity of lung cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
