Down-regulation of MSH2 expression by Hsp90 inhibition enhances cytotoxicity affected by tamoxifen in human lung cancer cells

Ko, Jen-Chung; Chiu, Hsien-Yi; Syu, Jhan-Jhang; Chen, Chien‐Yu; Jian, Yunting; Huang, Yi-Jhen; Wo, Ting-Yu; Jian, Yi-Jun; Chang, Po‐Yuan; Wang, Tai-Jing; Lin, Yun‐Wei

doi:10.1016/j.bbrc.2014.11.116

Cited by 10 publications

(8 citation statements)

References 19 publications

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“…Tamoxifen, an estrogen receptor antagonist, has been used as therapy against breast cancer [ 177 ] and could promote cell death in NSCLC [ 178 ]. The combined treatment of tamoxifen with 17-AAG promotes the cytotoxic effect and growth inhibition of tamoxifen, significantly decreasing the expression of MSH2 in human lung carcinoma ‎cells treated with tamoxifen [ 179 , 180 ].…”

Section: Role Of Hsp90 In the Genome Stability Maintenancementioning

confidence: 99%

Hsp90: A New Player in DNA Repair?

2015

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Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted.

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Section: Role Of Hsp90 In the Genome Stability Maintenancementioning

confidence: 99%

Hsp90: A New Player in DNA Repair?

2015

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“…Despite recent advances in surgery, radiation and medical treatments, the 5-year survival rate of patient with NSCLC remains one of the lowest among all major human cancers [2]. Recently, advances in molecular biology have led to an increased knowledge of the mechanisms underlying NSCLC development, especially in the PI3K/AKT signaling pathway [3,4]. The PI3K signaling pathway plays essential roles in cancer cell proliferation, survival, metabolism, motility and invasion.…”

Section: Introductionmentioning

confidence: 99%

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Wang

Zhong

et al. 2015

Med Oncol

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CC chemokine receptor-9 (CCR9) is highly expressed in non-small cell lung cancer (NSCLC) tissues and cell lines. However, the biological functions and the signals elicited by the interaction between CCR9 and its natural ligand CCL25 in NSCLC are unknown. Here, we selectively depleted CCR9 and inhibited CCR9-CCL25 interaction in NSCLC cells using small recombinant lentivirus-mediated miRNA, and investigated the tumorigenic effects in vitro and in vivo. Compromised CCR9-CCL25 interaction promoted apoptosis in NSCLC cells by activating phosphoinositide 3-kinase (PI3K)/Akt in vitro. In addition, we showed that CCR9-CCL25 interaction mediated the activation of the PI3K/Akt pathway in NSCLC cells, resulting in the up-regulation of anti-apoptotic proteins, as well as the down-regulation of apoptotic proteins in a PI3K-/Akt-dependent manner. These CCR9-CCL25-mediated effects were abrogated in the presence of a PI3K inhibitor (wortmannin 10 nM) or by inhibiting the CCR9-CCL25 interaction through CCR9 silencing, which also suggested that the biological function of CCR9-CCL25 was mainly regulated by PI3K. In vivo studies also demonstrated a significantly lower tumor burden in mice receiving CCR9-silence cells than those in mice receiving control cells. Together, these data suggested that CCR9-CCL25 interaction induced tumorigenesis of NSCLC cells and that this induction might be accomplished through the activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of CCR9-CCL25 interaction and provide clues for identifying novel therapeutic and preventive molecular markers for NSCLC.

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“…When that result was compared with the result of this study, LY and TAM were found to be more effective in MCF-7 cells compared to A2780 cells. In other previous studies, the co-treatment of LY and TAM significantly enhanced the cytotoxicity against lung and brain cancer cells compared to treatment with TAM alone [ 27 , 29 ].…”

Section: Discussionmentioning

confidence: 89%

“…The cytotoxicity of LY and TAM as single treatments and in combination were previously evaluated on A2780 (ovarian cancer) and MRC-5 (normal fibroblast). The IC 50 of LY were 21.2 µM and 35.7 µM, and for TAM were 10.4 µM and 11.4 µM, and for the combination of LY and TAM were 4.7 and 24.2 µM, respectively [ 26 , 27 , 28 ]. When that result was compared with the result of this study, LY and TAM were found to be more effective in MCF-7 cells compared to A2780 cells.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen and the PI3K Inhibitor: LY294002 Synergistically Induce Apoptosis and Cell Cycle Arrest in Breast Cancer MCF-7 Cells

et al. 2020

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Breast cancer is considered as one of the most aggressive types of cancer. Acquired therapeutic resistance is the major cause of chemotherapy failure in breast cancer patients. To overcome this resistance and to improve the efficacy of treatment, drug combination is employed as a promising approach for this purpose. The synergistic cytotoxic, apoptosis inducing, and cell cycle effects of the combination of LY294002 (LY), a phosphatidylinositide-3-kinase (PI3K) inhibitor, with the traditional cytotoxic anti-estrogen drug tamoxifen (TAM) in breast cancer cells (MCF-7) were investigated. LY and TAM exhibited potent cytotoxic effect on MCF-7 cells with IC50 values 0.87 µM and 1.02 µM. The combination of non-toxic concentration of LY and TAM showed highly significant synergistic interaction as observed from isobologram (IC50: 0.17 µM, combination index: 0.18, colony formation: 9.01%) compared to untreated control. The percentage of early/late apoptosis significantly increased after treatment of MCF-7 cells with LY and TAM combination: 40.3%/28.3% (p < 0.001), compared to LY single treatment (19.8%/11.4%) and TAM single treatment (32.4%/5.9%). In addition, LY and TAM combination induced the apoptotic genes Caspase-3, Caspase-7, and p53, as well as p21 as cell cycle promotor, and significantly downregulated the anti-apoptotic genes Bcl-2 and survivin. The cell cycle assay revealed that the combination induced apoptosis by increasing the pre-G1: 28.3% compared to 1.6% of control. pAKT and Cyclin D1 protein expressions were significantly more downregulated by the combination treatment compared to the single drug treatment. The results suggested that the synergistic cytotoxic effect of LY and TAM is achieved by the induction of apoptosis and cell cycle arrest through cyclin D1, pAKT, caspases, and Bcl-2 signaling pathways.

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Down-regulation of MSH2 expression by Hsp90 inhibition enhances cytotoxicity affected by tamoxifen in human lung cancer cells

Cited by 10 publications

References 19 publications

Hsp90: A New Player in DNA Repair?

Hsp90: A New Player in DNA Repair?

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Tamoxifen and the PI3K Inhibitor: LY294002 Synergistically Induce Apoptosis and Cell Cycle Arrest in Breast Cancer MCF-7 Cells

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