Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Srivastava, Amit Kumar; Han, Chunhua; Zhao, Ruihua; Cui, Tiantian; Dai, Yuntao; Mao, Charlene; Zhao, Weiqiang; Zhang, Xiaoli; Yu, Jianhua; Wang, Qi-En

doi:10.1073/pnas.1421365112

Cited by 157 publications

(173 citation statements)

References 53 publications

(63 reference statements)

Supporting

Mentioning

159

Contrasting

Order By: Relevance

“…We have recently determined the NER efficiency of ovarian CSCs, defined by either CD44+CD117+ or spheroid growing in serumfree culture, after treatment with cisplatin. Surprisingly, although ovarian CSCs exhibited resistance to cisplatin treatment compared to their corresponding bulk cancer cells, no increased capability to remove cisplatin-induced DNA lesions was found in these CSCs [49] . In contrast, we revealed an elevated expression of DNA polymerase η and constitutively high levels of mono-ubiquitylated PCNA in various ovarian CSCs, indicating that enhanced TLS could be responsible for cisplatin resistance in these cells [49] .…”

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 93%

“…Surprisingly, although ovarian CSCs exhibited resistance to cisplatin treatment compared to their corresponding bulk cancer cells, no increased capability to remove cisplatin-induced DNA lesions was found in these CSCs [49] . In contrast, we revealed an elevated expression of DNA polymerase η and constitutively high levels of mono-ubiquitylated PCNA in various ovarian CSCs, indicating that enhanced TLS could be responsible for cisplatin resistance in these cells [49] . The controversial observations of the DDR in CSCs indicate that enhanced DDR can be a contributor in been suggested to enhance the cytotoxicity of various antitumor agents [32] .…”

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 93%

“…Recently, the work in our lab revealed depleted miR-93 expression in ovarian CSCs, which is, at least partially, responsible for the upregulated DNA polymerase η expression. Transfection of miR-93 into ovarian CSCs increased their sensitivity to cisplatin treatment, probably through downregulation of DNA polymerase η and thus inhibition of TLS of CSCs [49] . These findings provide a new avenue to facilitate the eradication of CSCs by platinum-based chemotherapeutics.…”

Section: Targeting the Ddr To Facilitate Eradication Of Cscsmentioning

confidence: 99%

See 2 more Smart Citations

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

Self Cite

View full text Add to dashboard Cite

The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

show abstract

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 93%

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 93%

Section: Targeting the Ddr To Facilitate Eradication Of Cscsmentioning

confidence: 99%

See 1 more Smart Citation

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

Self Cite

View full text Add to dashboard Cite

show abstract

“…CSCs thus implying the involvement of a Polη-mediated TLS which seems to contribute to their observed resistance in cisplatin treatment [87]. Taken together, it can be speculated that hyperthermia can influence TLS as there is evidence for the existence of interactions between…”

Section: Translesion Dna Synthesis (Tls)mentioning

confidence: 96%

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

Mantso

Goussetis

Franco

et al. 2016

Seminars in Cancer Biology

View full text Add to dashboard Cite

Utilization of thermal therapy (hyperthermia) is defined as the application of exogenous heat induction and represents a concept that is far from new as it goes back to ancient times when heat was used for treating various diseases, including malignancies. Such therapeutic strategy has gained even more popularity (over the last few decades) since various studies have shed light into understanding hyperthermia's underlying molecular mechanism(s) of action. In general, hyperthermia is applied as complementary (adjuvant) means in therapeutic protocols combining chemotherapy and/or irradiation both of which can induce irreversible cellular DNA damage. Furthermore, according to a number of in vitro, in vivo and clinical studies, hyperthermia has been shown to enhance the beneficial effects of DNA targeting therapeutic strategies by interfering with DNA repair response cascades. Therefore, the continuously growing evidence supporting hyperthermia's beneficial role in cancer treatment can also encourage its application as a DNA repair mitigation strategy. In this review article, we aim to provide detailed information on how hyperthermia acts on DNA damage and repair pathways and thus potentially contributing to various adjuvant therapeutic protocols relevant to more efficient cancer treatment strategies.

show abstract

“…Increasing evidence has shown that dysregulation of these mutagenic TLS polymerases is frequently observed in a variety of cancers and could drive genomic instability and tumorigenesis (5). Recently, it has been reported that elevated levels of TLS components could enhance DNA repair capacity, which allow cancer cells to acquire a drugresistant phenotype (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling

et al. 2016

View full text Add to dashboard Cite

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol k, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol k in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol k disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression.Further investigation of the relationship between Pol k and temozolomide revealed that Pol k inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol k-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol k. Finally, we found that Pol k overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. Ó2016 AACR.

show abstract

Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

Cited by 157 publications

References 53 publications

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling

Contact Info

Product

Resources

About