Dataset Information

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

ABSTRACT: Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.

SUBMITTER: Liu YR

PROVIDER: S-EPMC5581080 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

Liu Yan-Rong YR Liang Lan L Zhao Jian Min JM Zhang Yang Y Zhang Min M Zhong Wei-Long WL Zhang Qiang Q Wei Jun-Jie JJ Li Meng M Yuan Jie J Chen Shuang S Zong Shu-Min SM Liu Hui-Juan HJ Meng Jing J Qin Yuan Y Sun Bo B Yang Lan L Zhou Hong-Gang HG Sun Tao T Yang Cheng C

Oncotarget 20170502 32

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenoca ...[more]

PMID: 28881781

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Project description:The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression.

Dataset Information

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

Publications

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

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