MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis
© The author(s)..
Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Journal of Cancer - 15(2024), 8 vom: 15., Seite 2306-2317 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Chunlin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Bicalutamide resistance |
|---|
| Anmerkungen: |
Date Revised 19.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.7150/jca.92379 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369851714 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369851714 | ||
| 003 | DE-627 | ||
| 005 | 20240319233159.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240318s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.7150/jca.92379 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1336.xml |
| 035 | |a (DE-627)NLM369851714 | ||
| 035 | |a (NLM)38495481 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Chunlin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis |
| 264 | 1 | |c 2024 | |
| 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 Revised 19.03.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © The author(s). | ||
| 520 | |a Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Bicalutamide resistance | |
| 650 | 4 | |a Ferroptosis | |
| 650 | 4 | |a Prostate cancer | |
| 650 | 4 | |a Prostate-specific antigen | |
| 650 | 4 | |a miRNA | |
| 700 | 1 | |a Yu, Haitao |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Xuesong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Zhenwei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Yuhua |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Gou, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yuanzhong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Guo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of Cancer |d 2010 |g 15(2024), 8 vom: 15., Seite 2306-2317 |w (DE-627)NLM201575388 |x 1837-9664 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g number:8 |g day:15 |g pages:2306-2317 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.7150/jca.92379 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |e 8 |b 15 |h 2306-2317 | ||