Estimation of ABCB1 concentration in plasma membrane

Mlejnek, Petr; Kosztyu, Petr; Doležel, Petr; Kimura, Yasuhisa; Čížková, Kateřina; Ruzickova, Eliska

doi:10.1002/jcb.29157

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…In terms of subcellular localization, P-gp is most commonly found on the cell surface, more specifically within the plasma membrane [36,37,64]. This is consistent with its function as an efflux pump.…”

Section: Tissue Localization Subcellular Localization Substratessupporting

confidence: 58%

Genetics of ABCB1 in Cancer

Skinner,

Palkar,

Hong

2023

Cancers

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ABCB1, also known as MDR1, is a gene that encodes P-glycoprotein (P-gp), a membrane-associated ATP-dependent transporter. P-gp is widely expressed in many healthy tissues—in the gastrointestinal tract, liver, kidney, and at the blood–brain barrier. P-gp works to pump xenobiotics such as toxins and drugs out of cells. P-gp is also commonly upregulated across multiple cancer types such as ovarian, breast, and lung. Overexpression of ABCB1 has been linked to the development of chemotherapy resistance across these cancers. In vitro work across a wide range of drug-sensitive and -resistant cancer cell lines has shown that upon treatment with chemotherapeutic agents such as doxorubicin, cisplatin, and paclitaxel, ABCB1 is upregulated. This upregulation is caused in part by a variety of genetic and epigenetic mechanisms. This includes single-nucleotide variants that lead to enhanced P-gp ATPase activity without increasing ABCB1 RNA and protein levels. In this review, we summarize current knowledge of genetic and epigenetic mechanisms leading to ABCB1 upregulation and P-gp-enhanced ATPase activity in the setting of chemotherapy resistance across a variety of cancers.

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Section: Tissue Localization Subcellular Localization Substratessupporting

confidence: 58%

Genetics of ABCB1 in Cancer

Skinner,

Palkar,

Hong

2023

Cancers

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“…We used the method described previously [34]. Briefly, cells were washed in ice cold PBS (pH 7.4) and then fixed using 4% paraformaldehyde in PBS for 15 min at laboratory temperature.…”

Section: Immunostaining Of Lamp1mentioning

confidence: 99%

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

2020

Self Cite

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Lysosomal sequestration of anticancer therapeutics lowers their cytotoxic potential, reduces drug availability at target sites, and contributes to cancer resistance. Only recently has it been shown that lysosomal sequestration of weak base drugs induces lysosomal biogenesis mediated by activation of transcription factor EB (TFEB) which, in turn, enhances their accumulation capacity, thereby increasing resistance to these drugs. Here, we addressed the question of whether lysosomal biogenesis is the only mechanism that increases lysosomal sequestration capacity. We found that lysosomal sequestration of some tyrosine kinase inhibitors (TKIs), gefitinib (GF) and imatinib (IM), induced expansion of the lysosomal compartment. However, an expression analysis of lysosomal genes, including lysosome-associated membrane proteins 1, 2 (LAMP1, LAMP2), vacuolar ATPase subunit B2 (ATP6V1B2), acid phosphatase (ACP), and galactosidase beta (GLB) controlled by TFEB, did not reveal increased expression. Instead, we found that both studied TKIs, GF and IM, induced lysosomal fusion which was dependent on nicotinic acid adenine dinucleotide phosphate (NAADP) mediated Ca2+signaling. A theoretical analysis revealed that lysosomal fusion is sufficient to explain the enlargement of lysosomal sequestration capacity. In conclusion, we demonstrated that extracellular TKIs, GF and IM, induced NAADP/Ca2+ mediated lysosomal fusion, leading to enlargement of the lysosomal compartment with significantly increased sequestration capacity for these drugs without apparent lysosomal biogenesis.

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A systems framework for investigating the roles of multiple transporters and their impact on drug resistance

di San Germano,

Krishnan

2024

Integrative Biology

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Efflux transporters are a fundamental component of both prokaryotic and eukaryotic cells, play a crucial role in maintaining cellular homeostasis, and represent a key bridge between single cell and population levels. From a biomedical perspective, they play a crucial role in drug resistance (and especially multi-drug resistance, MDR) in a range of systems spanning bacteria and human cancer cells. Typically, multiple efflux transporters are present in these cells, and the efflux transporters transport a range of substrates (with partially overlapping substrates between transporters). Furthermore, in the context of drug resistance, the levels of transporters may be elevated either due to extra or intracellular factors (feedforward regulation) or due to the drug itself (feedback regulation). As a consequence, there is a real need for a transparent systems-level understanding of the collective functioning of a set of transporters and their response to one or more drugs. We develop a systems framework for this purpose and examine the functioning of sets of transporters, their interplay with one or more drugs and their regulation (both feedforward and feedback). Using computational and analytical work, we obtain transparent insights into the systems level functioning of a set of transporters arising from the interplay between the multiplicity of drugs and transporters, different drug–transporter interaction parameters, sequestration and feedback and feedforward regulation. These insights transparently arising from the most basic consideration of a multiplicity of transporters have broad relevance in natural biology, biomedical engineering and synthetic biology. Insight, Innovation, Integration: Innovation: creating a structured systems framework for evaluating the impact of multiple transporters on drug efflux and drug resistance. Systematic analysis allows us to evaluate the effect of multiple transporters on one/more drugs, and dissect associated resistance mechanisms. Integration allows for elucidation of key cause-and-effect relationships and a transparent systems-level understanding of the collective functioning of transporters and their impact on resistance, revealing the interplay of key underlying factors. Systems-level insights include the essentially different behaviour of transporters as part of a group; unintuitive effects of influx; effects of elevated transporter-levels by feedforward and drug-induced mechanisms. Relevance: a systems understanding of efflux, their role in MDR, providing a framework/platform for use in designing treatment, and in synthetic biology design.

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Estimation of ABCB1 concentration in plasma membrane

Cited by 3 publications

References 34 publications

Genetics of ABCB1 in Cancer

Genetics of ABCB1 in Cancer

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

A systems framework for investigating the roles of multiple transporters and their impact on drug resistance

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