TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway
Introduction: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipola...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
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| Series: | Journal of Advanced Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123222000662 |
| _version_ | 1797961109875982336 |
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| author | Chi-Che Hsieh Yue-Chiu Su Kuan-Ying Jiang Takamichi Ito Ting-Wei Li Yumiko Kaku-Ito Shih-Tsung Cheng Li-Tzong Chen Daw-Yang Hwang Che-Hung Shen |
| author_facet | Chi-Che Hsieh Yue-Chiu Su Kuan-Ying Jiang Takamichi Ito Ting-Wei Li Yumiko Kaku-Ito Shih-Tsung Cheng Li-Tzong Chen Daw-Yang Hwang Che-Hung Shen |
| author_sort | Chi-Che Hsieh |
| collection | DOAJ |
| description | Introduction: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. Objectives: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. Methods: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. Results: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. Conclusions: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1. |
| first_indexed | 2024-04-11T00:54:17Z |
| format | Article |
| id | doaj.art-45f85d2e01b84468a49f262c71d68593 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-04-11T00:54:17Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-45f85d2e01b84468a49f262c71d685932023-01-05T06:23:42ZengElsevierJournal of Advanced Research2090-12322023-01-01434557TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathwayChi-Che Hsieh0Yue-Chiu Su1Kuan-Ying Jiang2Takamichi Ito3Ting-Wei Li4Yumiko Kaku-Ito5Shih-Tsung Cheng6Li-Tzong Chen7Daw-Yang Hwang8Che-Hung Shen9National Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanDepartment of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanDepartment of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JapanDepartment of Life Sciences, National Cheng Kung University, Tainan 704, TaiwanDepartment of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JapanDepartment of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Ph.D. Program in Tissue Engineering and Regenerative Medicine, Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan; Corresponding author at: National Institute of Cancer Research, National Health Research Institutes, No. 367, Sheng-Li Rd., North District, Tainan 70456, Taiwan.Introduction: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. Objectives: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. Methods: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. Results: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. Conclusions: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.http://www.sciencedirect.com/science/article/pii/S2090123222000662Acral melanomaTRPM1CaMKIICa2+ channel |
| spellingShingle | Chi-Che Hsieh Yue-Chiu Su Kuan-Ying Jiang Takamichi Ito Ting-Wei Li Yumiko Kaku-Ito Shih-Tsung Cheng Li-Tzong Chen Daw-Yang Hwang Che-Hung Shen TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway Journal of Advanced Research Acral melanoma TRPM1 CaMKII Ca2+ channel |
| title | TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway |
| title_full | TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway |
| title_fullStr | TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway |
| title_full_unstemmed | TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway |
| title_short | TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway |
| title_sort | trpm1 promotes tumor progression in acral melanoma by activating the ca2 camkiiδ akt pathway |
| topic | Acral melanoma TRPM1 CaMKII Ca2+ channel |
| url | http://www.sciencedirect.com/science/article/pii/S2090123222000662 |
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