Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma
© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association..
Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:114 |
|---|---|
| Enthalten in: |
Cancer science - 114(2023), 5 vom: 16. Mai, Seite 1943-1957 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Rao, Xinrui [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
DNA damage repair |
|---|
| Anmerkungen: |
Date Completed 04.05.2023 Date Revised 05.05.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/cas.15727 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM351536892 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM351536892 | ||
| 003 | DE-627 | ||
| 005 | 20231226051614.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/cas.15727 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1171.xml |
| 035 | |a (DE-627)NLM351536892 | ||
| 035 | |a (NLM)36642785 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Rao, Xinrui |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.05.2023 | ||
| 500 | |a Date Revised 05.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. | ||
| 520 | |a Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DNA damage repair | |
| 650 | 4 | |a POLQ | |
| 650 | 4 | |a lung cancer | |
| 650 | 4 | |a radioresistance | |
| 650 | 4 | |a tumorigenesis | |
| 700 | 1 | |a Xing, Biyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Zilong |e verfasserin |4 aut | |
| 700 | 1 | |a Bin, Yawen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yunshang |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yingzhuo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiaoshu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Chuangyan |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Wang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Weibin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Geng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Xiaorong |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Rui |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer science |d 2003 |g 114(2023), 5 vom: 16. Mai, Seite 1943-1957 |w (DE-627)NLM12479498X |x 1349-7006 |7 nnns |
| 773 | 1 | 8 | |g volume:114 |g year:2023 |g number:5 |g day:16 |g month:05 |g pages:1943-1957 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/cas.15727 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 114 |j 2023 |e 5 |b 16 |c 05 |h 1943-1957 | ||