Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover.

Ohkawa, Kiyoshi; Asakura, Tadashi; Takada, Koji; Sawai, Takahiro; Hashizume, Yukio; Okawa, Yutaka; Yanaihara, Nozomu

doi:10.3892/ijo.15.4.677

Cited by 11 publications

(12 citation statements)

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“…Bortezomib and MG-132, proteasome inhibitors, reportedly reduced the degree of the MDR in MCF-7/DOX cells, 24) and MG-132 apparently reversed the MDR of gastric cancer by inhibiting P-gp. 25) These findings suggest that proteasome inhibitors attenuate the expression of P-gp and induce 27) In the RPMI-8226/TP-110 cells, our results clearly indicate that a proteasome inhibitor, TP-110, is the substrate of ABCB1 (P-gp).…”

Section: Discussionsupporting

confidence: 49%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/ TP-110) cells and elucidated their resistance mechanisms. The IC 50 value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.

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Section: Discussionsupporting

confidence: 49%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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“…4). One early study suggested that calpain inhibitors increased ubiquitination of Pgp at the cell membrane, and in vitro proteolysis experiments showed that calpain can cleave Pgp (44). If and how calpain cleavage might stabilize Pgp at the cell membrane is currently unknown, and our data did not reveal evidence of this.…”

Section: Discussioncontrasting

confidence: 52%

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

Grieve

Gao

Hall

et al. 2016

Molecular and Cellular Biology

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Calpain is an intracellular Ca 2؉ -regulated protease system whose substrates include proteins involved in proliferation, survival, migration, invasion, and sensitivity to therapeutic drugs. Genetic disruption of calpain attenuated the tumorigenic potential of breast cancer cells and hypersensitized cells to 17AAG, an inhibitor of the molecular chaperone HSP90. Calpain-1 or -2 overexpression rendered cells resistant to 17AAG, whereas downregulation or inhibition of calpain-1/2 led to increased cell death in multiple breast cancer cell lines, including models of HER2 ؉ (SKBR3) and triple-negative basal-cell-like (MDA-MB-231) breast cancer. In an MDA-MB-231 orthotopic xenograft model, calpain knockdown or 17AAG treatment independently attenuated tumor growth and metastasis, while the combination was most effective. Calpain knockdown was associated with increased 17AAG-induced degradation of the HSP90 clients cyclin D1 and AKT and multidrug resistance protein 2, which correlated with increased expression of antimitogenic p27 KIP1 and proapoptotic BIM proteins. Like other therapeutics, 17AAG can be effluxed by specific ABC transporters. Calpain expression positively correlated with the expression of P glycoprotein in mouse embryonic fibroblasts. Importantly, we show that calpain affects ABC transporter function and efflux of clinically relevant doxorubicin. These observations provide a compelling rationale for exploring the combination of calpain inhibition with new or existing cancer therapeutics. Calpains are a family of intracellular calcium-dependent proteases. Of the 15 mammalian isoforms, calpain-1 and calpain-2 are ubiquitously expressed and have been most extensively studied (reviewed in reference 1). They are heterodimers consisting of isoform-specific catalytic subunits encoded by CAPN1 and CAPN2, respectively, and a common regulatory subunit encoded by CAPNS1. Heterodimerization is essential for both stability and enzymatic activity; hence, genetic disruption of CAPNS1 results in loss of both calpain-1 and -2 activities (2, 3).Elevated calpain expression or activity has been associated with multiple cancer types, including colon, liver, lung, prostate, ovarian, and breast cancers (reviewed in reference 4). Mechanistic understanding of calpain's involvement in cancer is confounded by its broad range of substrates, including signaling or structural proteins that regulate diverse cellular functions such as mitogenesis, migration, invasion, and death (1). Biomarker studies suggest a positive correlation between elevated calpain expression and a poor clinical outcome in breast cancer (5-7).Paradoxically, calpain is associated with prodeath (8, 9) or prosurvival (9-11), depending upon the physiologic context and specific challenges cells are exposed to. For example, calpain-mediated cleavage of PP2A supports activation of AKT and a prosurvival function in mouse embryonic fibroblasts (MEFs) (10), and in breast cancer cells and xenograft mouse models, knockdown of CAPN2 was associated with attenuated tumor growth...

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“…Serine protease cleavage of the linker region of isolated ABCB1 produces an *80 kDa peptide stimulating its ATPase activity, 47 while calpain proteolysis results in *98 and 69 kDa fragments that may impact ABCB1 turnover. 48 We also observed ABCC1 proteolytic fragments after TBI that were *90 and 50 kDa (Fig. 1).…”

Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 83%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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Adenosine triphosphate-binding cassette (ABC) transport proteins ABCC1 and ABCB1 (also known as multidrug resistance-associated protein 1 and p-glycoprotein, respectively), are key membrane efflux transporters of drugs and endogenous substrates, including in the brain. The impact of traumatic brain injury (TBI) on ABCC1 and ABCB1 expression in humans is unknown. We hypothesized that ABCC1 and ABCB1 expression would be altered in brain tissue from patients acutely after severe TBI. Archived TBI samples (n = 10) from our Brain Trauma Research Center and control samples (n = 7) from our Alzheimer Disease Research Center were obtained under Institutional Review Board approval. Protein was extracted from fresh frozen cortical brain tissue for Western blot analysis and sections were obtained from fixed cortical tissue for immunohistochemistry. Relative abundance of ABCC1 was increased in samples from TBI versus controls (2.8 -2.5 fold; p = 0.005). ABCC1 immunohistochemistry was consistent with Western blot data, with increased immunoreactivity in cerebral blood vessel walls, as well as cells with the morphological appearance of neurons and glia in TBI versus controls. Relative abundance of ABCB1 was similar between TBI and controls ( p = 0.76), and ABCB1 immunoreactivity was primarily associated with cerebral blood vessels in both groups. These human data show that TBI increases ABCC1 expression in the brain, consistent with possible implications for both patients receiving pharmacological inhibitors and/or substrates of ABCC1 after TBI.

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Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover.

Cited by 11 publications

References 0 publications

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

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