Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins

Horibe, Sayo; Matsuda, Akira; Tanahashi, Takao; Inoue, Jun; Kawauchi, Shoji; Mizuno, Shigeto; Ueno, Masaki; Takahashi, Kyohei; Maeda, Yusaku; Maegouchi, Tatsuya; Murakami, Yoshiki; Yumoto, Ryoko; Nagai, Junya; Takano, Mikihisa

doi:10.1016/j.lfs.2015.01.011

Cited by 38 publications

(28 citation statements)

References 15 publications

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“…The cell cycle alterations are in agreement with previously published work [48], showing that tumor initiating cells are prone to less G 2 /M-arrest after DNA-damaging treatment. Horibe et al showed that cisplatin resistance is linked to loss of G 2 /M arrest in cisplatin-resistant cells [49]. The p53 target gene product p21 that induces cell cycle arrest in G 2 /M-phase was up-regulated in sensitive and resistant cells after treatment with cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

et al. 2017

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The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

et al. 2017

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“…Si et al showed that EZH2 silencing may reverse tamoxifen resistance in MCF-7 breast cancer cell by regulating the cell cycle [7]. In lung cancer, the modification of cell cycle associated proteins was enhanced in cisplatin resistant A549 cells, which resulted in G2/M progression [8]. Hence, these findings about cell cycle-mediated chemoresistance in cancers highlight that cell cycle status may alter the response of tumor cells to chemotherapic agents.…”

Section: Ivyspringmentioning

confidence: 99%

B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A

Wang

et al. 2020

J. Cancer

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Colorectal cancer (CRC) is one of the most common malignancies, and chemoresistance is one of the key obstacles in the clinical outcome. Here, we studied the function of B7-H3 in regulating cell cycle-mediated chemoresistance in CRC. The ability of B7-H3 in regulating chemoresistance was investigated via cell viability, clonogenicity, apoptosis and cycle analysis in vitro. Moreover, the role of B7-H3/CDC25A axis in regulating chemoresistance in vivo in the xenograft tumor models by intraperitoneal injection of oxaliplatin (L-OHP) and CDC25A inhibitors. The correlation between B7-H3 and CDC25A was examined in the CRC patients by immunohistochemistry (IHC) and pathological analyses. We found that B7-H3 could effectively enhance the resistance to a chemotherapeutic drug (oxaliplatin or 5-fluorouracil) via CDC25A. B7-H3 regulated the expression of CDC25A by the STAT3 signaling pathway in CRC cells. Furthermore, overexpression of B7-H3 enhanced chemoresistance by reducing the G2/M phase arrest in a CDC25A-dependent manner. Silencing CDC25A or treatment with CDC25A inhibitor could reverse the B7-H3-induced chemoresistance of cancer cells. Moreover, both B7-H3 and CDC25A were significantly upregulated in CRC samples compared with normal adjacent tissues and that the levels correlated with tumor stage. CDC25A was positively correlated with B7-H3 expression in this cohort. Taken together, our findings provide an alternative mechanism by which CRC cells can acquire chemoresistance via the B7-H3/CDC25A axis.

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“…Low drug perfusion in hypoxic interior of tumors changes the cytotoxicity and the associated signaling networks. Cisplatin is a commonly used drug for the treatment of non-small cell lung cancer and patients often develop resistance to cisplatin over the course of therapy and multiple mechanisms have been attributed to the resistance, including hypoxia [31, 32]. On-going research efforts aim to overcome this chemo-resistance, however, the outcomes have been limited.…”

Section: Discussionmentioning

confidence: 99%

Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells

et al. 2016

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Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.

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Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins

Cited by 38 publications

References 15 publications

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A

Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells

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