Ku80 correlates with neoadjuvant chemotherapy resistance in human lung adenocarcinoma, but reduces cisplatin/pemetrexed-induced apoptosis in A549 cells

Shang, Bin; Jia, Yongsheng; Chen, Gang; Wang, Zhou

doi:10.1186/s12931-017-0545-6

Cited by 10 publications

(10 citation statements)

References 27 publications

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“…XRCC5, also known as Ku80, is encoded by XRCC5 gene located on human chromosome 2q33‐35 . It has been reported that XRCC5 has a specific upregulation in lung adenocarcinoma tissue compared with adjacent normal lung tissue, which is correlated with poor survival and cisplatin resistance, making it a potential biomarker . Increased expression of XRCC5 can also protect cancer cells from radiation‐mediated cell death .…”

Section: Discussionmentioning

confidence: 99%

“…60 It has been reported that XRCC5 has a specific upregulation in lung adenocarcinoma tissue compared with adjacent normal lung tissue, which is correlated with poor survival and cisplatin resistance, making it a potential biomarker. 61,62 Increased expression of XRCC5 can also protect cancer cells from radiation-mediated cell death. 63,64 These results support XRCC5 as a good target for the development of novel chemotherapy for treating cancer cells with drug resistance.…”

Section: Bfgf Was Highly Expressed and Secreted To Promote Dox Resimentioning

confidence: 99%

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Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Hsieh

Huang

Lin

et al. 2020

Molecular Carcinogenesis

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Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High‐grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell‐cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox‐treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral‐mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X‐ray repair cross‐complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

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Section: Discussionmentioning

confidence: 99%

Section: Bfgf Was Highly Expressed and Secreted To Promote Dox Resimentioning

confidence: 99%

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Hsieh

Huang

Lin

et al. 2020

Molecular Carcinogenesis

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“…Moreover, by evaluating multiple NSCLC cell lines after treatment with pemetrexed, MSH2 levels were demonstrated to be increased and the cytotoxicity of pemetrexed was found to be enhanced by the knockdown of MSH2 (P<0.010) (57). Similar to MSH2, pemetrexed-treated A549 cell viability was found to be augmented by silenced Ku80, one of the two subunits of Ku protein (58).…”

Section: Dna Damage and Repairmentioning

confidence: 96%

Mechanisms of resistance to pemetrexed in non-small cell lung cancer

Liang¹,

Lu²,

Chen³

et al. 2019

Transl Lung Cancer Res

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Currently, lung cancer has remained the most common cause of cancer death while non-small cell lung cancer (NSCLC) accounts for the most of all lung cancer cases. Regardless of multiple existing managements, chemotherapy regimens are still the mainstay of treatment for NSCLC, where pemetrexed has shown cytotoxic activity and has increasingly been used, especially for advanced cases. However, chemoresistance may inhibit clinical efficacy after long-term use. Mechanisms responsible for chemo-resistance to pemetrexed in NSCLC are plethoric but can be separated into two categories to be discussed: tumor cells and their interactions with drugs. Phenomena relevant to tumor cells such as oncogene or oncoprotein alterations, DNA synthesis, DNA repair, and tumor cell biology behavior are discussed, as well as processes associated with drug dynamics, including drug uptake, drug elimination, and antifolate polyglutamylation. This review will focus on clinical trials and the basic biomedical mechanisms of NSCLC treated with pemetrexed and will describe the underlying mechanisms of resistance to facilitate more efficient clinical therapies to treat patients.

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“…In clinical lung adenocarcinoma specimens, chemoresistant tumors exhibited higher protein expression levels of XRCC5; therefore, XRCC5 could predict the responsiveness and prognosis in patients with lung cancer ( 25 ). Furthermore, XRCC5 overexpression was found to increase the resistance to chemotherapy drugs, while XRCC5 knockdown augmented drug sensitivity in lung cancer cells ( 26 ). In thyroid carcinoma, XRCC5 protein expression levels in carcinoma tissues were significantly higher compared with that in non-neoplastic adjacent tissue and XRCC5 knockdown decreased malignancy in thyroid cancer cells ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma

Lee

Yang

Huang³

et al. 2021

Oncol Lett

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Drug resistance and disease recurrence are important contributors for the poor prognosis of glioblastoma multiforme (GBM). Temozolomide (TMZ), the standard chemotherapy for GBM treatment, can methylate DNA and cause the formation of double-strand breaks (DSBs). X-ray repair cross complementing 5 (XRCC5), also known as Ku80 or Ku86, is required for the repair of DSBs. The present study identified novel determinants that sensitize cells to TMZ, using an array-based short hairpin (sh)RNA library. Then, cBioportal, Oncomine, and R2 databases were used to analyze the association between gene expression levels and clinical characteristics. Subsequently, lentiviral shRNA or pCMV was used to knockdown or overexpress the gene of interest, and the effects on TMZ sensitivity were determined using a MTT assay and western blot analysis. TMZ-resistant cells were also established and were used in in vitro and in vivo experiments to analyze the role of the gene of interest in TMZ resistance. The results indicated that XRCC5 was effective in enhancing TMZ cytotoxicity. The results from the bioinformatics analysis revealed that XRCC5 mRNA expression levels were associated with clinical deterioration and lower overall survival rates. In addition, XRCC5 knockdown could significantly increase TMZ sensitivity in GBM cells, while XRCC5 overexpression caused the cancer cells to be resistant to TMZ. Both the in vivo and in vitro experiments showed that TMZ treatment could induce expression of XRCC5 in TMZ-resistant cells. Taken together these findings suggested that XRCC5 could be a promising target for GBM treatment and could also be used as a diagnostic marker for refractory GBM.

show abstract

Ku80 correlates with neoadjuvant chemotherapy resistance in human lung adenocarcinoma, but reduces cisplatin/pemetrexed-induced apoptosis in A549 cells

Cited by 10 publications

References 27 publications

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Mechanisms of resistance to pemetrexed in non-small cell lung cancer

Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma

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