The 44-kDa Pim-1 Kinase Phosphorylates BCRP/ABCG2 and Thereby Promotes Its Multimerization and Drug-resistant Activity in Human Prostate Cancer Cells

Xie, Yingqiu; Xu, Kexin; Linn, Douglas E.; Yang, Xi; Guo, Zhiyong; Shimelis, Hermela; Nakanishi, Takeo; Ross, Douglas D.; Chen, Hegang; Fazli, Ladan; Gleave, Martin; Qiu, Yun

doi:10.1074/jbc.m707773200

Cited by 176 publications

(182 citation statements)

References 22 publications

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“…As stated earlier, estradiol was shown to downregulate BCRP expression in ERα-positive cancer cells by decreasing BCRP protein synthesis and maturation (185) or in brain capillaries through a nongenomic pathway (187). Pim-1 kinase phosphorylates BCRP and promotes its dimerization and plasma membrane trafficking (196). BCRP protein expression can also be decreased by long-term exposure (>24 h) of cells to certain compounds (197).…”

Section: Regulation Of Bcrp Expressionmentioning

confidence: 92%

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

519

387

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Abstract. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrugresistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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Section: Regulation Of Bcrp Expressionmentioning

confidence: 92%

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

519

387

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“…As SP cells have a high drug efflux capacity owing to functional expression of ABC transporters such as BCRP (ABCG2) and P-glycoprotein (Pgp/ ABCB1) (Hirschmann-Jax et al, 2004), T-ICs in the SP may be more relevant to drug resistance than CD44 þ /CD24 Àlow /Lin À and ALDH1 þ T-ICs. In fact, HER2 is a predictive marker for responses to drugs that are effluxed through BCRP and/or Pgp, including cyclophosphamide, methotrexate and fluorouracil, (Menard et al, 2001;Wolff et al, 2007), docetaxel (Xie et al, 2008), as well as endocrine therapies, particularly tamoxifen (Konecny et al, 2003). Therefore, the activation of drug-resistant SP cells could provide an explanation for the poor response of HER2-positive and luminal-type tumours to cytotoxic chemotherapy.…”

mentioning

confidence: 99%

Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling

et al. 2010

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BACKGROUND: The expression of side-population (SP) cells and their relation to tumour-initiating cells (T-ICs) have been insufficiently studied in breast cancer (BC). We therefore evaluated primary cell cultures derived from patients and a panel of human BC cell lines with luminal-or basal-molecular signatures for the presence of SP and BC stem cell markers. METHODS: The SPs from luminal-type BC were analysed for BC T-IC characteristics, including human epidermal growth factor receptor 2 (HER2), ERa, IGFBP7 expression and their ability to initiate tumours in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice. Pharmacological modulators were used to assess the effects of HER2 signalling and breast cancer-resistance protein (BCRP) expression on SPs. RESULTS: The SP was more prevalent in the luminal subtype of BC compared with the basal subtype. HER2 expression was significantly correlated with the occurrence of an SP (r 2 ¼ 0.75, P ¼ 0.0003). Disappearance of SP in the presence of Ko143, a specific inhibitor of the ATP-binding cassette transporter BCRP, suggests that BCRP is the predominant transporter expressed in this population. The SP also decreased in the presence of HER2 signalling inhibitors AG825 or trastuzumab, strengthening the notion that HER2 contributed to the SP phenotype, likely through downstream AKT signalling. The SP cells from luminal-type MCF-7 cells with enforced expression of HER2, and primary cells with luminal-like properties from a BC patient, displayed enrichment in cells capable of repopulating tumours in NOD/SCID mice. Engraftment of SP cells was inhibited by pretreatment with AG825 or by in vivo treatment with trastuzumab. INTERPRETATION: Our findings indicate an important role of HER2 in regulating SP and hence T-ICs in BC, which may account for the poor responsiveness of HER2-positive BCs to chemotherapy, as well as their aggressiveness.

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“…64 On the other hand, BRCP was shown to be expressed in both cell lines, while MRP-2 was only found in PC3 cells. 65,66 One possible explanation for the increased cytotoxicity following the combination treatment, despite the redundancy of the proteins targeted, is that the small TKIs are also known inhibitors of these efflux pumps. Nilotinib has been identified as an inhibitor of the activity of the P-gp and the BCRP proteins, while sorafenib reduces the expression of P-gp proteins.…”

mentioning

confidence: 99%

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

Archibald

Pritchard

Nehoff

et al. 2016

IJN

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Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene- co -maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.

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The 44-kDa Pim-1 Kinase Phosphorylates BCRP/ABCG2 and Thereby Promotes Its Multimerization and Drug-resistant Activity in Human Prostate Cancer Cells

Cited by 176 publications

References 22 publications

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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