Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells
<p>Abstract</p> <p>Background</p> <p>While platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2011-03-01
|
| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/10/1/24 |
| _version_ | 1828468152744280064 |
|---|---|
| author | Wani Gulzar Huang Yi-Wen Han Chunhua Milum Keisha Wang Qi-En Thomale Jürgen Wani Altaf A |
| author_facet | Wani Gulzar Huang Yi-Wen Han Chunhua Milum Keisha Wang Qi-En Thomale Jürgen Wani Altaf A |
| author_sort | Wani Gulzar |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>While platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in conferring cisplatin resistance, targeting of DNA repair pathways is an effective stratagem for overcoming cisplatin resistance. This study was designed to delineate the role of nucleotide excision repair (NER), the principal mechanism for the removal of cisplatin-induced DNA intrastrand crosslinks, in cisplatin resistance and reveal the impact of DNA repair interference on cisplatin sensitivity in human ovarian cancer cells.</p> <p>Results</p> <p>We assessed the inherent NER efficiency of multiple matched pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines and their expression of NER-related factors at mRNA and protein levels. Our results showed that only the cisplatin-resistant ovarian cancer cell line PEO4 possessed an increased NER capacity compared to its inherently NER-inefficient parental line PEO1. Several other cisplatin-resistant cell lines, including CP70, CDDP and 2008C13, exhibited a normal and parental cell-comparable NER capacity for removing cisplatin-induced DNA intrastrand cross-links (Pt-GG). Concomitant gene expression analysis revealed discordance in mRNA and protein levels of NER factors in various ovarian cancer cell lines and NER proteins level were unrelated to the cisplatin sensitivity of these cell lines. Although knockdown of NER factors was able to compromise the NER efficiency, it only caused a minimal effect on cisplatin sensitivity. On the contrary, downregulation of BRCA2, a critical protein for homologous recombination repair (HRR), significantly enhanced the efficacy of cisplatin in killing ovarian cancer cell line PEO4.</p> <p>Conclusion</p> <p>Our studies indicate that the level of NER factors in ovarian cancer cell lines is neither a determinant of their NER capacity nor of the sensitivity to cisplatin, and suggest that manipulation of the HRR but not the NER factor expression provides an effective strategy for sensitizing cisplatin-resistant tumors to platinating agents.</p> |
| first_indexed | 2024-12-11T04:19:04Z |
| format | Article |
| id | doaj.art-b82a88bf7525450fb3b17b37ee82e240 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-11T04:19:04Z |
| publishDate | 2011-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-b82a88bf7525450fb3b17b37ee82e2402022-12-22T01:21:11ZengBMCMolecular Cancer1476-45982011-03-011012410.1186/1476-4598-10-24Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cellsWani GulzarHuang Yi-WenHan ChunhuaMilum KeishaWang Qi-EnThomale JürgenWani Altaf A<p>Abstract</p> <p>Background</p> <p>While platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in conferring cisplatin resistance, targeting of DNA repair pathways is an effective stratagem for overcoming cisplatin resistance. This study was designed to delineate the role of nucleotide excision repair (NER), the principal mechanism for the removal of cisplatin-induced DNA intrastrand crosslinks, in cisplatin resistance and reveal the impact of DNA repair interference on cisplatin sensitivity in human ovarian cancer cells.</p> <p>Results</p> <p>We assessed the inherent NER efficiency of multiple matched pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines and their expression of NER-related factors at mRNA and protein levels. Our results showed that only the cisplatin-resistant ovarian cancer cell line PEO4 possessed an increased NER capacity compared to its inherently NER-inefficient parental line PEO1. Several other cisplatin-resistant cell lines, including CP70, CDDP and 2008C13, exhibited a normal and parental cell-comparable NER capacity for removing cisplatin-induced DNA intrastrand cross-links (Pt-GG). Concomitant gene expression analysis revealed discordance in mRNA and protein levels of NER factors in various ovarian cancer cell lines and NER proteins level were unrelated to the cisplatin sensitivity of these cell lines. Although knockdown of NER factors was able to compromise the NER efficiency, it only caused a minimal effect on cisplatin sensitivity. On the contrary, downregulation of BRCA2, a critical protein for homologous recombination repair (HRR), significantly enhanced the efficacy of cisplatin in killing ovarian cancer cell line PEO4.</p> <p>Conclusion</p> <p>Our studies indicate that the level of NER factors in ovarian cancer cell lines is neither a determinant of their NER capacity nor of the sensitivity to cisplatin, and suggest that manipulation of the HRR but not the NER factor expression provides an effective strategy for sensitizing cisplatin-resistant tumors to platinating agents.</p>http://www.molecular-cancer.com/content/10/1/24 |
| spellingShingle | Wani Gulzar Huang Yi-Wen Han Chunhua Milum Keisha Wang Qi-En Thomale Jürgen Wani Altaf A Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells Molecular Cancer |
| title | Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| title_full | Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| title_fullStr | Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| title_full_unstemmed | Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| title_short | Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| title_sort | differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells |
| url | http://www.molecular-cancer.com/content/10/1/24 |
| work_keys_str_mv | AT wanigulzar differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT huangyiwen differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT hanchunhua differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT milumkeisha differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT wangqien differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT thomalejurgen differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells AT wanialtafa differentialcontributoryrolesofnucleotideexcisionandhomologousrecombinationrepairforenhancingcisplatinsensitivityinhumanovariancancercells |