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  • American Association for Cancer Research (AACR)  (8)
  • 1
    Online Resource
    Online Resource
    Abstract 3008: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3008-3008
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3008-3008
    Abstract: Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. And ABC activities is also intimately linked to epithelial mesenchymal transition and metastasis. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by directly fueling ABC transporters and increase its drug efflux activities. However, whether extracellular ATP can induce change in the expression of ABC transporters and the underlying mechanisms remain unclear. Our results from quantitative reverse transcription PCR and flow cytometry show that extracellular ATP significantly alters mRNA levels and cell surface expression of ABC transporters. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. On-going studies include identification of mechanisms for the extracellular ATP-induced drug resistance via ABC transporters. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhancing anticancer efficacy of chemotherapeutics and targeted drugs. Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3008.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3008
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Abstract 1521: New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of metastasis
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1521-1521
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1521-1521
    Abstract: Metastasis is estimated to be responsible for more than 90% of all cancer-related deaths. Metastasis is initiated by induction of epithelial-mesenchymal transition (EMT) of cancer cells, but factors and mechanisms involved in EMT are far from being fully elucidated. Intratumoral extracellular ATP (eATP), at levels of 100-700 μM or 103 to 104 times higher than in normal tissues, has been known to induce epithelial-mesenchymal-transition (EMT) of cancer cells via purinergic receptor signaling. However, the exact induction mechanisms are far from fully known. We previously described that eATP is internalized by cancer cells in vitro and in vivo by macropinocytosis in human non-small cell lung cancer cells, drastically elevates intracellular ATP levels, enhances cell proliferation and resistance to anticancer drugs. In this study, we tested the hypothesis that eATP and macropinocytosis-internalized eATP also induces EMT and other early steps of metastasis. Here we report that eATP, at the concentrations reported in tumors, potently induces expression of matrix metallopeptidases (MMPs), detachment, EMT, migration, and invasion of lung cancer cells. The induction was independent of TGF-β and semi-independent of P2X7 activation. eATP performs these functions not only extracellularly, but also intracellularly after being macropinocytically internalized to further enhance P2X7-mediated EMT, filopodia formation and other early steps of metastasis. The knockout of the macropinocytosis-associated SNX5 gene significantly reduces macropinocytosis and slows down tumor growth in nude mice. Collectively, these results show that eATP functions on these processes not only from outside of cancer cells but also inside after being macropinocytotically internalized. These findings which shed light on eATP's initiator and effector roles in almost every step in early metastasis call for rethinking and rebalancing energy equations of intracellular biochemical reactions and the Warburg effect, and identify eATP and macropinocytosis as novel targets for potentially slowing down EMT, preventing metastasis, and reducing metastasis-related death in cancer patients. Citation Format: Yanyang Cao, Xuan Wang, Maria Evers, Yunsheng Li, Haiyun Zhang, Xiaozhuo Chen. New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1521.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1521
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Online Resource
    Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS Mutations in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 8 ( 2022-04-14), p. 1640-1650
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 8 ( 2022-04-14), p. 1640-1650
    Abstract: Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking. Experimental Design: We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non–small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations. Results: In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors. Conclusions: This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-2719
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Abstract 405: A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 405-405
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 405-405
    Abstract: Drug resistance are responsible for most relapses and up to 90% of cancer related death. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism. In tumor microenvironment, intratumoral extracellular ATP (eATP) levels are 1,000 times or more higher than those in corresponding normal tissues. Our previous studies have shown that eATP can be taken up by cancer cell via macropinocytosis, leading to substantial increase in intracellular ATP levels. We found that this high intracellular ATP levels contribute to drug resistance in several ways: first, it directly fueled and enhanced drug-pumping activity of major ATP-binding cassette (ABC) multidrug transporters, which are located in plasma membrane and can pump out a wide range of substrates including anticancer drugs, leading to reduced intracellular drug retention. Secondly, ATP treatment upregulated gene expression of the major ABC transporters, and this gene regulatory effect of ATP was comparable to TGF-beta, which is a well-established epithelial-mesenchymal transition (EMT) inducer, and EMT is known to induce ABC transporter expression and drug resistance. Moreover, eATP treatment led to an increase in intracellular glutathione (GSH) levels, probably by enhancing GSH synthesis. Increased GSH levels have been described to significantly contribute to drug resistance. We also found eATP altered cellular redox state, which potentially stimulates EMT. Furthermore, we performed RNA-sequencing and identified several genes that may serve as downstream factors of eATP in promoting EMT and drug resistance. We are currently investigating the roles of these genes by knocking down gene expression or knocking out these genes. Citation Format: Haiyun Zhang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 405.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-405
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Abstract 1306: Primary NK cells and luciferase expressing reporter cell lines for use in developing ADCC assays for immuno-oncology drug screening
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1306-1306
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1306-1306
    Abstract: Immuno-oncology is one of the fastest growing fields in oncology, and cancer immunotherapy in recent years represents a milestone in the treatment of cancer. Natural killer (NK) cells are potent innate effectors capable of targeting and killing virally infected and malignant cells. The use of monoclonal antibodies (mAbs) targeting tumor antigens triggers antibody-dependent cellular cytotoxicity (ADCC) by NK cells, which has shown prominent clinical efficacy in clearing tumors in cancer patients. Therefore, the development of tumor cell targeting mAbs and biologics dictate a clear need for human cell-based models to evaluate antibody efficacy. In this study, human PBMCs and purified NK cells from healthy donors are used to develop an ADCC assay. The NK cells purified from PBMCs are & gt;90% CD45+ CD56+, express high levels of CD16, and NK activation markers such NKG2A, KIR2DL1, NKp44 upon activation. The activated NK cells exhibit both strong direct and antibody-dependent cytotoxicity. Genotyping for FcγRIIIa receptor F and V variant is also performed for cells isolated from different donors, which is the genetic polymorphism that affects ADCC response. In addition, we employ a portfolio of luciferase reporter tumor cell lines to evaluate NK cell direct killing and ADCC targeted killing. These include K562, Wil2S, BT474, A431, A375 parental, and CRISPR edited A375 KRAS mutant cell lines engineered to express luc2 reporter. The commonly targeted cell surface markers, such as CD20, Her2, and EGFR, are highly expressed within this panel of target tumor cell lines. We validate the ADCC assay system through testing the efficacy for some of the well-known mAb biologics such as anti-CD20, anti-HER2, and anti-EGFR. After co-culture of activated primary NK cells with luciferase reporter target cell lines and the addition of dilutions of ADCC and isotype control antibodies, we are able to show target cell specific and dose-dependent killing effects. The luciferase reporter provides great convenience in measuring target cell killing without having to use radioactive 51Cr release assay or pre-label the cells with calcein. This data demonstrates the utility of primary NK cells along with a portfolio of well characterized luciferase reporter tumor cell line to develop “custom” designed ADCC assays for studying NK cell immune response and screening for biological drugs for cancer immunotherapy. Citation Format: Haiyun Liu, Brian Della Fera, John Foulke, Luping Chen, Fang Tian. Primary NK cells and luciferase expressing reporter cell lines for use in developing ADCC assays for immuno-oncology drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1306.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1306
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 1378: Identification of genomic regions associated with temozolomide resistance in glioblastoma through analysis of histone marks on chromatin
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1378-1378
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1378-1378
    Abstract: Glioblastoma (GBM) is an aggressive and fatal primary brain tumor. Temozolomide (TMZ) is a critical component of the standard care of newly diagnosed GBM patients, but unfortunately preexisting primary resistance and rapid emergence of secondary resistance invariably limits the therapeutic benefit of TMZ in GBM. Prior studies have identified genetic and epigenetic alterations that can modulate TMZ sensitivity and treatment outcome. However, comprehensive analysis of histone marks and knowledge of epigenetic regulation of genes associated with TMZ sensitivity or resistance is lacking. To identify epigenetic states associated with TMZ resistance, we performed an epigenetic profiling of eight different histone marks in GBM xenografts. Using chromatin immunoprecipitation combined with high throughput sequencing (ChIP-seq), distribution of H3K4me1, H3K4me3, H3K9ac, H3K9me2, H3K9me3, H3K27ac, H3K27me3 and H3K36me3 histone marks was compared in a panel of GBM patient-derived xenograft sub-lines derived by treating TMZ sensitive GBM12 tumors with placebo (n=2 sublines) or temozolomide (n=6 sub-lines) and then propagating resulting recurrent tumors. Our analysis revealed that H3K4me1 and H3K27ac modification patterns varied globally across individual sub-lines, while distribution of H3K4me3, H3K36me3 histone marks was specifically altered in discrete genomic regions in resistant sub-lines depending on the mechanisms of resistance. To find how epigenetic modifications affect TMZ sensitivity, we analyzed ChIP-Seq data using Hidden Markov Model to test if one or a combination of histone marks relates to TMZ resistance. The effect of histone modifications on transcription was simultaneously determined by RNA sequencing. These analyses helped identify specific histone modifications which could be functionally related to TMZ resistance. Through these analyses we have identified 1142 genomic regions governed by a specific epigenetic pattern. We subsequently analyzed a candidate genomic region on top of the list. By using Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated nucleases 9 system (CRISPR/Cas9 system), we have generated clones from an intrinsically TMZ resistant SKMG3 cell line with deletion up to four-kilo base genomic region. Clonogenic growth assays showed that deletion of this genomic region enhanced TMZ sensitivity, reducing the IC50 from 186 μM to less than 60μM, p & lt;0.05. This finding indicates that this genomic region is functionally related with TMZ sensitivity. Taken together, our study reveals epigenetic modifications related to TMZ resistance in GBM cells and a specific genomic region involved in regulating TMZ sensitivity. The analysis of epigenetic state at this genomic region could potentially be useful in predicting treatment response and may help in designing TMZ sensitizing therapy in GBM. Citation Format: Xiaoyue Chen, Haiyun Gan, Jeong Heong Lee, Dong Fang, Gaspar Kitange, Jann Sarkaria, Zhiguo Zhang. Identification of genomic regions associated with temozolomide resistance in glioblastoma through analysis of histone marks on chromatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1378. doi:10.1158/1538-7445.AM2017-1378
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1378
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
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  • 7
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    Online Resource
    Abstract 1108: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1108-1108
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1108-1108
    Abstract: Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism1. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues2. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by fueling ABC transporters and increase its efflux activities3. However, whether extracellular ATP can indeed enhance efflux of drugs, and the underlying mechanism besides providing energy remain unclear. Our current study results showed extracellular ATP decreased intracellular accumulation and thereby enhanced efflux of 3H-labeled chemotherapeutic drug and targeted drug in human cancer cells. The results of quantitative reverse transcription PCR, western blot and immunofluorescence microscopy demonstrated that extracellular ATP can also significantly upregulate ABC transporters at mRNA and protein levels, and change the intracellular localization of the latter. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhance anticancer efficacy of chemotherapeutics and targeted drugs. 1. Pavlova N, Thompson C. Cell Metab. (2016) 23:27-47 2. Falzoni S, et al., Interface Focus. (2013) 3: 20120101 3. Wang X, et al., Oncotarget. (2017) 8(50):87860-87877 Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1108.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1108
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    Abstract 2846: Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2846-2846
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2846-2846
    Abstract: Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival from drug treatment (1). However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types, including non-small cell lung cancer, breast cancer, colon, liver cancer, and pancreatic cancer (2). In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme, strongly suggesting that the resistance is mediated at least in part by micropinocytosis (and therefore ATP internalization) (2). The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells, as well as phosphorylation of PDGFRα and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells, increasing cell cycle progression and decreasing drug-induced apoptosis. Similar phosphorylation upregulations were found in A549 tumors. The resistance was not significantly affected by purinergic receptor-mediated signaling. These results demonstrate, for the first time, that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets. References 1.Qian, Y. et al. Mol Cancer Res 14(11); 1087-1096 (2016) 2.Wang, X. et al. Oncotarget 8, 87860-87877 (2017). Citation Format: Xiaozhuo Chen, Xuan Wang, Haiyun Zhang, Yanrong Qian, Yunsheng Li, Yanyang Cao, Pratik Shriwas. Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2846.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2846
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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