MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Rocco, Alba; Compare, Debora; Liguori, Eleonora; Cianflone, Alessandra; Pirozzi, Giuseppe; Tirino, Virginia; Bertoni, Alessandra; Santoriello, Margherita; Garbi, Corrado; D’Armiento, Maria; Staibano, Stefania; Nardone, Gerardo

doi:10.1038/labinvest.2012.100

Cited by 36 publications

(21 citation statements)

References 36 publications

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“…Second, our study reveals a novel in vivo physiological function of ABCB5 in maintaining quiescent LSCs, through ABCB5-dependent regulation of apoptotic signalling pathways. This parallels the known anti-apoptotic function of the ABCB5 homologue ABCB1, shown to be mediated through cross-talk with Bcl-x 14 . Finally, our finding that ABCB5 regulates stem cell maintenance is highly relevant to the study of additional ABCB5-expressing normal stem cell populations in other tissues 6,10 and of slow-cycling ABCB5 + cancer stem cells, in which this role might represent one mechanism of multidrug resistance to cell-cycle-specific agents 10,11,15 .…”

supporting

confidence: 60%

ABCB5 is a limbal stem cell gene required for corneal development and repair

Ksander

Kolovou

Wilson

et al. 2014

Nature

235

220

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Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs)1–3, and LSC deficiency is a major cause of blindness worldwide4. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts5, a gene allowing for prospective LSC enrichment has not been identified so far5. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5)6,7 marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs2 in mice and p63α-positive LSCs8 in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.

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supporting

confidence: 60%

ABCB5 is a limbal stem cell gene required for corneal development and repair

Ksander

Kolovou

Wilson

et al. 2014

Nature

235

220

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“…The levels of GCS mRNA and protein are elevated 4-fold in approximately 80% of metastatic breast cancers, and GCS overexpression is associated with lymph node metastasis in bladder cancers (25,26). In addition, P-gp overexpression is associated with unfavorable prognosis in leukemia, lymphoma, and breast, colon, pancreatic, and gastric cancers (8)(9)(10). The clinical significance of P-gp overexpression has also been studied in HNC.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, P-gp regulates cancer proliferation, invasion, and caspase-dependent cell death (6,7). P-gp overexpression in tumors is associated with poor prognosis in several types of cancers (8)(9)(10). The upregulation of rafts and caveolae, including that of the glucosphingolipid-enriched constituents of microdomains, represents another multidrug resistance (MDR) mechanism (11).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

Roh

Kim

Park

et al. 2015

Molecular Cancer Therapeutics

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Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or D,L-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P ¼ 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacologic inhibition of GCS induced accumulation of increased ceramide levels. GCS inhibition increased cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in cisplatin-resistant HNC.

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“…The study showed that when the tumor cells surface increased expression MDR1 significantly, the accumulation of drugs reduced in cells; when blocked the function of MDR1, the cell resistance would obviously reversed. Moreover, MDR1 could redistribute the intracellular drug, pump the drug out of the cell and reduce intracellular drug accumulation (Hoffmann et al, ; Rocco et al, ).…”

Section: Discussionmentioning

confidence: 99%

The Role of Phenethyl Isothiocyanate on Bladder Cancer ADM Resistance Reversal and Its Molecular Mechanism

Tang

Lin

2013

The Anatomical Record

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Adramycin (ADM) resistance is an essential aspect of bladder cancer treatment failure and phenethyl isothiocyanate (PEITC) has been found to exhibit antitumor properties; however, the effect and potential mechanism of PEITC on bladder cancer ADM resistance reversal is not fully clear. The aim of this study was to explore the role of PEITC in bladder cancer cells ADM resistance reversal and the underlying molecular mechanisms. In this report, we identified the role of PEITC on ADM resistance reversal of human bladder carcinoma T24/ADM cells, including an increased drug sensitivity to ADM, cell apoptosis rates, intracellular accumulation of , an increased expression of DNA topoisomerase II (Topo-II), and a decreased expression of multidrug resistance gene (MDR1), multidrug resistance-associated protein (MRP1), bcl-2 and glutathione s transferase p (GST-p).We also found that there was a decreased expression of NF-jB, Survivin, Twist, and p-Akt, and an increased expression of PTEN and p-JNK after PEITC treatment for T24/ ADM cells. The results indicated that PEITC might be used as a potential therapeutic strategy to ADM resistance through blocking Akt and activating MAPK pathway in human bladder carcinoma. Anat Rec, 296:899-906, 2013. V C 2013 Wiley Periodicals, Inc. Key words: adramycin; bladder cancer; drug resistanceBladder cancer is one of the most common malignant tumors which are threatening human's life and health seriously (Oosterlinck and Decaestecker, 2012). Surgery assisted by chemotherapy has become the main therapeutic schemes for bladder cancer. Reasonable chemotherapy could use the anti-cancer drugs cytotoxicity to the maximum, but bladder cancer was palindromic in the biological characteristics, and its relapse rate has been high. One of the reasons was the generation of anti-cancer drug resistance. Therefore, the resistance of anti-cancer drug has become a major obstacle in the chemotherapy of bladder cancer, and it must clarify the drug resistance mechanisms to eliminate the anti-cancer drug resistance of tumor cells. Like most malignant bladder cancer, it showed multidrug resistance (Multidrug Resistance, MDR) in anticancer drug resistance. Resistance mechanisms of tumor cells was quite complex, and summarized the followings: (1) drug transporting or uptaking barriers; (2) drug activation barriers; (3) target enzyme changes in the quantity and quality; (4) metabolic pathways increased; (5) decomposing enzyme increased; (6) repair mechanisms increased; (7) the cell membrane glycoprotein specific in excluding drugs increased; (8) DNA chains cross-linked reduced; (9) hormone receptor reduction or loss of function, and so on (Kunze et al., 2012).The generation of multidrug resistance in tumor cells has become a major cause of failure in tumor

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MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Cited by 36 publications

References 36 publications

ABCB5 is a limbal stem cell gene required for corneal development and repair

ABCB5 is a limbal stem cell gene required for corneal development and repair

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

The Role of Phenethyl Isothiocyanate on Bladder Cancer ADM Resistance Reversal and Its Molecular Mechanism

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