PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas
Objective: The BRAF inhibitor, vemurafenib, has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations. While the initial response to vemurafenib is usually excellent, the majority of patients eventually develop resistance and metastatic disease. However, the underly...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2022-08-01
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| Series: | Cancer Biology & Medicine |
| Subjects: | |
| Online Access: | https://www.cancerbiomed.org/content/19/8/1211 |
| _version_ | 1828353317265211392 |
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| author | Junling Shen Jilong Yang Lei Sang Rui Sun Weiyu Bai Chao Wang Yan Sun Jianwei Sun |
| author_facet | Junling Shen Jilong Yang Lei Sang Rui Sun Weiyu Bai Chao Wang Yan Sun Jianwei Sun |
| author_sort | Junling Shen |
| collection | DOAJ |
| description | Objective: The BRAF inhibitor, vemurafenib, has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations. While the initial response to vemurafenib is usually excellent, the majority of patients eventually develop resistance and metastatic disease. However, the underlying molecular mechanism remains elusive. The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance. Methods: Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays. The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed. Invadopodia cell invasion, and a Ca2+ assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression. A mouse model was used to assess the effects of PYK2 on melanoma metastasis. Results: Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells, and PYK2 was shown to regulate invadopodia formation in melanoma cells. Vemurafenib triggered invadopodia formation by activation of PYK2. Inhibition of PYK2 with either shRNA or the small molecule inhibitor, PF562711, dramatically reduced vemurafenib-induced invadopodia formation. Furthermore, knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo. Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage (P = 0.002), metastasis (P < 0.001), and Clark grade (P < 0.001), and were also associated with short overall survival [hazard ratio (HR) = 3.304, P = 0.007] and progression-free survival (HR = 2.930, P = 0.001). Conclusions: PYK2 mediated vemurafenib-induced melanoma cell migration and invasion. Inhibition of PYK2 resensitized melanoma cells to vemurafenib. Phospho-PYK2 was a prognostic biomarker in melanoma patients. |
| first_indexed | 2024-04-14T02:05:58Z |
| format | Article |
| id | doaj.art-a4c7194c32844833b7fac0b3b5911027 |
| institution | Directory Open Access Journal |
| issn | 2095-3941 |
| language | English |
| last_indexed | 2024-04-14T02:05:58Z |
| publishDate | 2022-08-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj.art-a4c7194c32844833b7fac0b3b59110272022-12-22T02:18:40ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412022-08-011981211122310.20892/j.issn.2095-3941.2020.0294PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomasJunling Shen0Jilong Yang1Lei Sang2Rui Sun3Weiyu Bai4Chao Wang5Yan Sun6Jianwei Sun7Center for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, ChinaTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaCenter for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, ChinaCenter for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, ChinaCenter for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, ChinaTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaCenter for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, ChinaObjective: The BRAF inhibitor, vemurafenib, has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations. While the initial response to vemurafenib is usually excellent, the majority of patients eventually develop resistance and metastatic disease. However, the underlying molecular mechanism remains elusive. The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance. Methods: Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays. The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed. Invadopodia cell invasion, and a Ca2+ assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression. A mouse model was used to assess the effects of PYK2 on melanoma metastasis. Results: Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells, and PYK2 was shown to regulate invadopodia formation in melanoma cells. Vemurafenib triggered invadopodia formation by activation of PYK2. Inhibition of PYK2 with either shRNA or the small molecule inhibitor, PF562711, dramatically reduced vemurafenib-induced invadopodia formation. Furthermore, knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo. Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage (P = 0.002), metastasis (P < 0.001), and Clark grade (P < 0.001), and were also associated with short overall survival [hazard ratio (HR) = 3.304, P = 0.007] and progression-free survival (HR = 2.930, P = 0.001). Conclusions: PYK2 mediated vemurafenib-induced melanoma cell migration and invasion. Inhibition of PYK2 resensitized melanoma cells to vemurafenib. Phospho-PYK2 was a prognostic biomarker in melanoma patients.https://www.cancerbiomed.org/content/19/8/1211stim1pyk2invadopodiainvasionmelanomavemurafenib |
| spellingShingle | Junling Shen Jilong Yang Lei Sang Rui Sun Weiyu Bai Chao Wang Yan Sun Jianwei Sun PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas Cancer Biology & Medicine stim1 pyk2 invadopodia invasion melanoma vemurafenib |
| title | PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas |
| title_full | PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas |
| title_fullStr | PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas |
| title_full_unstemmed | PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas |
| title_short | PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas |
| title_sort | pyk2 mediates the braf inhibitor vermurafenib induced invadopodia formation and metastasis in melanomas |
| topic | stim1 pyk2 invadopodia invasion melanoma vemurafenib |
| url | https://www.cancerbiomed.org/content/19/8/1211 |
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