Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells

Cheng, Ran; Liu, Ya‐Jing; Cui, Junwei; Yang, Mi; Liu, Xiaoling; Zhan, Wang; Zhu, Lizhang; Lu, Siyi; Zou, Li; Wu, Xiaoqin; Li, Yuxia; Zhou, You; Fang, Zhengyu; Wei, Wei

doi:10.18632/oncotarget.16325

Cited by 40 publications

(37 citation statements)

References 50 publications

(65 reference statements)

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“…The expression of cyclin D1 is increased in different types of tumor tissues (46). The present results were consistent with these studies (41)(42)(43)(44)(45)(46), which indicated that telmisartan inhibited signaling via the PI3K/AKT pathway in A549 cells, and reduced the phosphorylation of mTOR, p70S6K and cyclin D1. In summary, the downregulation of the PI3K/AKT pathway may have contributed to the inhibitory effect of telmisartan on A549 cells.…”

Section: Discussionsupporting

confidence: 91%

Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway

Zhang

Wang

2018

Oncol Lett

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Abstract. Expression of angiotensin II (Ang II), a key biological peptide in the renin-angiotensin system, is closely associated with the occurrence and development of cancer. Ang II binds two receptor subtypes, the Ang II type 1 receptor (AT1R) and the AT2R, to mediate a series of biological effects. Telmisartan, a specific AT1R blocker, has been reported to have potential as an anticancer drug for treating renal cancer. In the present study, whether telmisartan had an effect on non-small cell lung cancer (NSCLC) cell proliferation and migration was investigated. The Cell Counting kit-8 assay revealed that telmisartan significantly inhibited the growth of the NSCLC A549 cell line in a time-and dose-dependent manner. In a transwell assay, telmisartan significantly inhibited cellular invasion and migration. Furthermore, it was determined that the expression of the anti-apoptotic protein B-cell lymphoma was decreased, and that of the pro-apoptotic proteins caspase-3 and Bcl-associated X increased in the A549 cells treated with telmisartan. Additionally, levels of phosphorylated RAC serine/threonine-protein kinase (p-AKT), p-mechanistic target of rapamycin, p70-S6 kinase and cyclin D1 was decreased in the telmisartan-treated group. Therefore, the current study reveals that telmisartan-induced NSCLC apoptosis may be regulated via the phosphoinositide 3-kinase/AKT signaling pathway, which indicates that it may be a potential novel drug for clinical NSCLC treatment. IntroductionLung cancer, the most common type of cancer, has the highest morbidity rate among all types of malignancies worldwide (1,2), accounting for 30% of all incidences of cancer-associated mortality (3). In clinical practice, the two major types of lung cancer are small cell lung cancer (SCLC) and non-SCLC (NSCLC) (4), of which NSCLC accounts for ~80% of all lung cancer cases (5). Current therapies for NSCLC include chemotherapy, radiotherapy, targeted therapy and surgery, which are used alone or in combination (6). Despite the use of these therapies, the overall 5-year survival rate of NSCLC remains low, at 15% (7). Owing to the development of drug resistance and the severe side effects experienced by patients, effective and safe novel agents are required for the treatment of NSCLC (1).Angiotensin II (Ang II), a key biological peptide in the renin-angiotensin system, is a vasoconstrictor that controls cardiovascular function and renal homeostasis (8). Ang II receptor blockers (ARBs) are extensively used as anti-hypertensive drugs (9). Studies have reported that angiogenesis is essential for tumor progression and metastasis (10,11). Furthermore, studies have demonstrated that ARBs have the potential possibility to restrain the growth of several types of cancer cells (12,13). Ang II binds two receptor subtypes, the Ang II type 1 receptor (AT1R) and the Ang II type 2 receptor (AT2R), to mediate a series of biological effects (14). AT1R mediates the main functions of Ang II, including tumor growth and angiogenesis (15). Treatment with telmisartan, a spe...

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Section: Discussionsupporting

confidence: 91%

Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway

Zhang

Wang

2018

Oncol Lett

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“…It's well known that aspirin depresses cell proliferation in many cancers [29][30][31][32][33][34]. To test the effects of aspirin on liver cancer cells, we performed cell viability, colony-formation and EdU assays in HepG2 and H7402 cells with different concentrations of aspirin.…”

Section: Aspirin Inhibits the Proliferation Of Liver Cancer Cells In mentioning

confidence: 99%

Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism

et al. 2018

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Aspirin can efficiently inhibit liver cancer growth, but the mechanism is poorly understood. In this study, we report that aspirin modulates glucose uptake through downregulating glucose transporter 1 (GLUT1), leading to the inhibition of hepatoma cell proliferation. Our data showed that aspirin significantly decreased the levels of reactive oxygen species (ROS) and glucose consumption in hepatoma cells. Interestingly, we identified that GLUT1 and HIF1α could be decreased by aspirin. Mechanically, we demonstrated that the -1008/-780 region was the regulatory element of transcriptional factor NF-κB in GLUT1 promoter by luciferase report gene assays. PDTC, an inhibitor of NF-κB, could suppress the expression of GLUT1 in HepG2 and H7402 cells, followed by affecting the levels of ROS and glucose consumption. CoCl-activated HIF1α expression could slightly rescue the GLUT1 expression inhibited by aspirin or PDTC, suggesting that aspirin depressed GLUT1 through targeting NF-κB or NF-κB/HIF1α signaling. Moreover, we found that GLUT1 was highly expressed in clinical HCC tissues relating to their paired adjacent normal tissues. Importantly, we observed that high level of GLUT1 was significantly correlated with the poor relapse-free survival of HCC patients by analysis of public data. Functionally, overexpression of GLUT1 blocked the PDTC-induced or aspirin-induced inhibition of glucose metabolism in HepG2 cells. Conversely, aspirin failed to work when GLUT1 was stably knocked down in the cells. Administration of aspirin could depress the growth of hepatoma cells through controlling GLUT1 in vitro and in vivo. Thus, our finding provides new insights into the mechanism by which aspirin depresses liver cancer.

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“…MYC is upregulated in the tamoxifen‐resistant breast cancer cell line MCF7/TAM, and these cells are more sensitive to tamoxifen after MYC knockout. ER‐positive tumors with CCND1 amplification are not sensitive to tamoxifen …”

Section: Introductionmentioning

confidence: 99%

SIRT4 enhances the sensitivity of ER‐positive breast cancer to tamoxifen by inhibiting the IL‐6/STAT3 signal pathway

Xing

et al. 2019

Cancer Medicine

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Recent advances in endocrine therapy have improved the prospects for estrogen receptor‐positive breast cancer. Tamoxifen is an effective drug for patients with estrogen receptor‐positive breast cancer, but the development of resistance is common. Therefore, discovering ways to enhance the sensitivity of cancer cells to tamoxifen may help improve breast cancer treatment. We studied the biological role of sirtuin 4 (SIRT4) in tamoxifen‐treated MCF7 and T47D cells. The levels of the MYC proto‐oncogene (MYC) and cyclin D1 (CCND1) were detected by western blotting and quantitative reverse transcription‐polymerase chain reaction in breast cancer cells with SIRT4 overexpression or depletion. Immunofluorescence and western blotting were used to assess the phosphorylation status of signal transducer and activator of transcription 3 (STAT3). SIRT4 overexpression decreased the half maximal inhibitory concentration of tamoxifen in MCF7 and T47D cells, while its depletion increased it. Thus, SIRT4 enhances the sensitivity of breast cancer cells to tamoxifen. Moreover, western blotting revealed decreased STAT3 phosphorylation after SIRT4 transfection. The transcription and translation of MYC and CCND1, target genes of the STAT3 pathway, were also blocked. Immunofluorescence revealed that pathway activation and nuclear STAT4 translocation were suppressed when SIRT4 was overexpressed. Furthermore, the effects of SIRT4 overexpression or depletion on proliferation could be offset by STAT3 activation or inhibition. Taken together, these results demonstrate that SIRT4 enhances the tamoxifen sensitivity of breast cancer cells by inhibiting the STAT3 signaling pathway. With this knowledge, therapeutic strategies with reduced drug resistance risk may be developed.

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Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells

Cited by 40 publications

References 50 publications

Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway

Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway

Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism

SIRT4 enhances the sensitivity of ER‐positive breast cancer to tamoxifen by inhibiting the IL‐6/STAT3 signal pathway

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