Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells
Platelet-derived growth factor receptor (PDGFR) plays an essential role in the proliferation and invasion of malignant cancer cells. However, the functional role of PDGFR alpha (PDGFRA) in HER2-positive (HER2+) breast cancer has not been fully clarified yet. Thus, the objective of this study was to...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/3/675 |
| _version_ | 1797613383755759616 |
|---|---|
| author | Sangmin Kim Hyungjoo Kim Yisun Jeong Daeun You Sun Young Yoon Eunji Lo Seok Jin Nam Jeong Eon Lee Seok Won Kim |
| author_facet | Sangmin Kim Hyungjoo Kim Yisun Jeong Daeun You Sun Young Yoon Eunji Lo Seok Jin Nam Jeong Eon Lee Seok Won Kim |
| author_sort | Sangmin Kim |
| collection | DOAJ |
| description | Platelet-derived growth factor receptor (PDGFR) plays an essential role in the proliferation and invasion of malignant cancer cells. However, the functional role of PDGFR alpha (PDGFRA) in HER2-positive (HER2+) breast cancer has not been fully clarified yet. Thus, the objective of this study was to investigate the clinical significance of PDGFRA and the therapeutic potential of PDGFR inhibitors as part of an effort to overcome trastuzumab (TRZ) resistance. Aberrant PDGFRA expression is closely associated with decreased survival in HER2+ breast cancers. Therefore, we established BT474 trastuzumab-sensitive (TRZ_S) and trastuzumab-resistant (TRZ_R) cells to investigate the association between PDGFR signaling and TRZ resistance. We found that PDGFRA was significantly upregulated in the BT474 TRZ_R cells. In addition, IL-6 expression, which was also found to be upregulated in the TRZ_R cells, was induced by PDGFC, a ligand of PDGFR. Next, we investigated the effects of ponatinib and sunitinib, PDGFR inhibitors, on the BT474 TRZ_R and HCC1954 (TRZ-resistant cell line) cells. These inhibitors decreased cell viability and migration in a dose-dependent manner. Additionally, IL-6 expression was decreased by ponatinib in both the BT474 TRZ_R and HCC1954 cells. In contrast, IL-6 was not suppressed by TRZ, implying that the PDGFRA/STAT3/IL-6 axis is associated with resistance to TRZ. In addition, we found that STAT3 and ERK phosphorylation were increased in the BT474 TRZ_R cells. IL-6 expression was suppressed by a STAT3 inhibitor, indicating that IL-6 expression is modulated downstream of STAT3. Taken together, these results suggest that PDGFRA could serve as a therapeutic target to overcome TRZ resistance. |
| first_indexed | 2024-03-11T06:55:05Z |
| format | Article |
| id | doaj.art-fec3c4a85b394698a146bf5582aebf74 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T06:55:05Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-fec3c4a85b394698a146bf5582aebf742023-11-17T09:43:57ZengMDPI AGBiomedicines2227-90592023-02-0111367510.3390/biomedicines11030675Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer CellsSangmin Kim0Hyungjoo Kim1Yisun Jeong2Daeun You3Sun Young Yoon4Eunji Lo5Seok Jin Nam6Jeong Eon Lee7Seok Won Kim8Department of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaDepartment of Breast Cancer Center, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of KoreaPlatelet-derived growth factor receptor (PDGFR) plays an essential role in the proliferation and invasion of malignant cancer cells. However, the functional role of PDGFR alpha (PDGFRA) in HER2-positive (HER2+) breast cancer has not been fully clarified yet. Thus, the objective of this study was to investigate the clinical significance of PDGFRA and the therapeutic potential of PDGFR inhibitors as part of an effort to overcome trastuzumab (TRZ) resistance. Aberrant PDGFRA expression is closely associated with decreased survival in HER2+ breast cancers. Therefore, we established BT474 trastuzumab-sensitive (TRZ_S) and trastuzumab-resistant (TRZ_R) cells to investigate the association between PDGFR signaling and TRZ resistance. We found that PDGFRA was significantly upregulated in the BT474 TRZ_R cells. In addition, IL-6 expression, which was also found to be upregulated in the TRZ_R cells, was induced by PDGFC, a ligand of PDGFR. Next, we investigated the effects of ponatinib and sunitinib, PDGFR inhibitors, on the BT474 TRZ_R and HCC1954 (TRZ-resistant cell line) cells. These inhibitors decreased cell viability and migration in a dose-dependent manner. Additionally, IL-6 expression was decreased by ponatinib in both the BT474 TRZ_R and HCC1954 cells. In contrast, IL-6 was not suppressed by TRZ, implying that the PDGFRA/STAT3/IL-6 axis is associated with resistance to TRZ. In addition, we found that STAT3 and ERK phosphorylation were increased in the BT474 TRZ_R cells. IL-6 expression was suppressed by a STAT3 inhibitor, indicating that IL-6 expression is modulated downstream of STAT3. Taken together, these results suggest that PDGFRA could serve as a therapeutic target to overcome TRZ resistance.https://www.mdpi.com/2227-9059/11/3/675PDGFRAIL-6trastuzumab resistanceHER2+ breast cancer |
| spellingShingle | Sangmin Kim Hyungjoo Kim Yisun Jeong Daeun You Sun Young Yoon Eunji Lo Seok Jin Nam Jeong Eon Lee Seok Won Kim Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells Biomedicines PDGFRA IL-6 trastuzumab resistance HER2+ breast cancer |
| title | Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells |
| title_full | Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells |
| title_fullStr | Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells |
| title_full_unstemmed | Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells |
| title_short | Suppression of Platelet-Derived Growth Factor Receptor-Alpha Overcomes Resistance to Trastuzumab through STAT3-Dependent IL-6 Reduction in HER2-Positive Breast Cancer Cells |
| title_sort | suppression of platelet derived growth factor receptor alpha overcomes resistance to trastuzumab through stat3 dependent il 6 reduction in her2 positive breast cancer cells |
| topic | PDGFRA IL-6 trastuzumab resistance HER2+ breast cancer |
| url | https://www.mdpi.com/2227-9059/11/3/675 |
| work_keys_str_mv | AT sangminkim suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT hyungjookim suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT yisunjeong suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT daeunyou suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT sunyoungyoon suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT eunjilo suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT seokjinnam suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT jeongeonlee suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells AT seokwonkim suppressionofplateletderivedgrowthfactorreceptoralphaovercomesresistancetotrastuzumabthroughstat3dependentil6reductioninher2positivebreastcancercells |