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STAT3 but Not HIF-1? Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

ABSTRACT: Hypoxia-induced chemoresistance (HICR) is a well-recognized phenomenon, and in many experimental models, hypoxia inducible factor-1? (HIF-1?) is believed to be a key player. We aimed to better understand the mechanism underlying HICR in a triple negative breast cancer cell line, MDA-MB-231, with a focus on the role of HIF-1?. In this context, the effect of hypoxia on the sensitivity of MDA-MB-231 cells to cisplatin and their stem-like features was evaluated and the role of HIF-1? in both phenomena was assessed. Our results showed that hypoxia significantly increased MDA-MB-231 resistance to cisplatin. Correlating with this, intracellular uptake of cisplatin was significantly reduced under hypoxia. Furthermore, the stem-like features of MDA-MB-231 cells increased as evidenced by the significant increases in the expression of ATP-binding cassette (ABC) drug transporters, the proportion of CD44?/CD24- cells, clonogenic survival and cisplatin chemoresistance. Under hypoxia, both the protein level and DNA binding of HIF-1? was dramatically increased. Surprisingly, siRNA knockdown of HIF-1? did not result in an appreciable change to HICR. Instead, signal transducer and activator of transcription 3 (STAT3) activation was found to be important. STAT3 activation may confer HICR by upregulating ABC transporters, particularly ABCC2 and ABCC6. This study has demonstrated that, in MDA-MB-231 cells, STAT3 rather than HIF-1? is important in mediating HICR to cisplatin.

SUBMITTER: Soleymani Abyaneh H

PROVIDER: S-EPMC5664076 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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STAT3 but Not HIF-1α Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Soleymani Abyaneh Hoda H Gupta Nidhi N Radziwon-Balicka Aneta A Jurasz Paul P Seubert John J Lai Raymond R Lavasanifar Afsaneh A

Cancers 20171014 10

Hypoxia-induced chemoresistance (HICR) is a well-recognized phenomenon, and in many experimental models, hypoxia inducible factor-1α (HIF-1α) is believed to be a key player. We aimed to better understand the mechanism underlying HICR in a triple negative breast cancer cell line, MDA-MB-231, with a focus on the role of HIF-1α. In this context, the effect of hypoxia on the sensitivity of MDA-MB-231 cells to cisplatin and their stem-like features was evaluated and the role of HIF-1α in both phenome ...[more]

PMID: 29036915

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Project description:Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

Dataset Information

STAT3 but Not HIF-1? Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Publications

STAT3 but Not HIF-1α Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Similar Datasets

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