Arsenic trioxide inhibits cell growth and motility via up-regulation of let-7a in breast cancer cells

Shi, Ying; Cao, Tong; Huang, Hua; Lian, Chaoqun; Yang, Ying; Wang, Zhiwei; Ma, Jia; Xia, Jun

doi:10.1080/15384101.2017.1387699

Cited by 34 publications

(23 citation statements)

References 54 publications

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“…In our study, down-expression level of hsa-let-7a was detected in UL compared to normal myometrium (p <0.001; r=0.365). hsa-let-7 microRNA family act as tumor suppressors and have been associated with poor prognosis in more than 20 different tumor types (Esquela-Kerscher et al, 2008;Guo et al, 2017;Shi et al, 2017;reviewed by Balzeau et al, 2017). Two studies in UL have reported upregulation of many hsa-let-7 family members, including hsa-let-7a, hsa-let-7b and hsa-let-7c (Wang et al, 2007;Zavadil et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

Mello

Barros-Filho

Abreu

et al. 2018

MHR: Basic Science of Reproductive Medicine

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BACKGROUND: Uterine Leiomyoma (UL) is the most common mesenchymal benign tumor associated with several clinical symptoms and elevated number of hysterectomies. The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, FH and COL4A5-COL4A6, pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored. METHODS: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b. RESULTS: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1: 18 UL). The analysis of RT-qPCR revealed a significant HMGA2 overexpression (p<0.001) in UL in comparison with NM. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (p<0.001) and negatively correlated to HMGA2 expression levels (P<0.05) in UL. CONCLUSION: HMGA2 overexpression was detected in a significant number of MED12 mutated UL, suggesting that these alterations can coexist. Furthermore, five miRNAs were pointed out as potential regulators of HMGA2 expression in UL.

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Section: Discussionmentioning

confidence: 99%

MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

Mello

Barros-Filho

Abreu

et al. 2018

MHR: Basic Science of Reproductive Medicine

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“…21,22 Due to the close relationship between glucose metabolism and cell proliferation, we speculated that let-7a-5p may inhibit the aerobic glycolysis and proliferation of breast cancer. 21,22 Due to the close relationship between glucose metabolism and cell proliferation, we speculated that let-7a-5p may inhibit the aerobic glycolysis and proliferation of breast cancer.…”

Section: Let-7a-5p Inhibits Aerobic Glycolysis and Proliferation Ofmentioning

confidence: 99%

PKM2 promotes glucose metabolism through a let‐7a‐5p/Stat3/hnRNP‐A1 regulatory feedback loop in breast cancer cells

Yao

Yuan

et al. 2018

J of Cellular Biochemistry

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Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let‐7a‐5p/Stat3/hnRNP‐A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)‐A1 expression, hnRNP‐A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let‐7a‐5p, which functionally targets Stat3, whereas hnRNP‐A1 blocks the biogenesis of let‐7a‐5p to counteract its ability to downregulate the Stat3/hnRNP‐A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP‐A1/PKM2 by let‐7a‐5p is verified using a breast cancer. These results suggest that let‐7a‐5p, Stat3, and hnRNP‐A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention.

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“…Arsenic trioxide (As 2 O 3 ) (ATO) is a metalloid with potent antineoplastic effects in several types of cancer especially acute promyelocytic leukemia and breast cancer. [12,13] ATO-dependent effect is thought to include the generation of reactive oxygen species (ROS) leading to the activation of proapoptotic pathways in different cancer cells. [14] Also, ATO is reported to activate the c-Jun N-terminal kinase (JNK) signaling and inhibit the AKT activity in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Combination of arsenic trioxide and cisplatin synergistically inhibits both hexokinase activity and viability of Ehrlich ascites carcinoma cells

Mansour

Ibrahim

Shalaan

et al. 2019

J Biochem & Molecular Tox

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Hexokinase‐2 is overexpressed in several carcinomas including breast cancer to sustain energy for rapidly dividing cells and associates with chemoresistance. However, the impact of chemo drugs (alone or in combination) on hexokinase activity and autophagic cell death is unclear. In this report, we used an in vivo murine adenocarcinoma model to validate the effects of As2O3 and cisplatin on hexokinase activity and autophagic cancer cell death. We found that the two drugs inhibit hexokinase activity and induce autophagic marker, beclin 1 expression. Interestingly, combining As2O3 with cisplatin synergistically enhanced these effects and alleviated oxidative stress often encountered in As2O3 treatment. Altogether, our data provide direct evidence that inhibition of hexokinase activity and induction of autophagic cell death are mediating the antineoplastic effects of As2O3 and cisplatin. Our findings raise the potential of combining As2O3 with cisplatin as an approach to augment cisplatin‐induced cell death and combat cisplatin chemoresistance in cancer.

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Arsenic trioxide inhibits cell growth and motility via up-regulation of let-7a in breast cancer cells

Cited by 34 publications

References 54 publications

MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

PKM2 promotes glucose metabolism through a let‐7a‐5p/Stat3/hnRNP‐A1 regulatory feedback loop in breast cancer cells

Combination of arsenic trioxide and cisplatin synergistically inhibits both hexokinase activity and viability of Ehrlich ascites carcinoma cells

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