Article ; Online: Aberrant expression of TMEM205 signaling promotes platinum resistance in ovarian cancer: An implication for the antitumor potential of DAP compound.
2021 Volume 164, Issue 1, Page(s) 136–145
Abstract: Introduction: TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated.: Methods: TMEM205 ... ...
| Abstract | Introduction: TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated. Methods: TMEM205 expression was evaluated in platinum-sensitive (PS) versus platinum resistant (PR) ovarian cancer cell lines and patient serum/tissues. Exosomal efflux of platinum was evaluated with inductively coupled plasma mass spectrometry (ICP-MS) after pre-treatment with small molecule inhibitors (L-2663/L-2797) of TMEM205 prior to treatment with platinum. Cytotoxicity of combination treatment was confirmed in vitro and in an in vivo model. Results: TMEM205 expression was 10-20 fold higher in PR compared to PS ovarian cancer cell lines, serum samples, and tissues. Co-localization with CD1B was confirmed by in-situ proximity ligation assay suggesting that TMEM205 may mediate PR via the exosomal pathway. Exosomal secretion was significantly increased 5-10 fold in PR cell lines after treatment with carboplatin compared to PS cell lines. Pre-treatment with L-2663 prior to carboplatin resulted in significantly increased intracellular concentration of fluorescently-labeled cisplatin and decreased exosomal efflux of platinum. Decreased cell survival and tumor growth in vitro and in vivo was observed when PR cells were treated with a combination of L-2663 with carboplatin compared to carboplatin alone. Conclusion: TMEM205 appears to be involved in the development of PR in ovarian cancer through the exosomal efflux of platinum agents. This study provides pre-clinical evidence that TMEM205 could serve as a possible biomarker for PR as well as a therapeutic target in combination with platinum agents. |
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| MeSH term(s) | Animals ; Female ; Humans ; Mice ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carboplatin/pharmacology ; Carboplatin/therapeutic use ; Cell Line, Tumor/drug effects ; Cell Line, Tumor/metabolism ; Disease Models, Animal ; Drug Resistance, Neoplasm/drug effects ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/drug effects ; Membrane Proteins/metabolism ; Mice, Nude ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism | |||||
| Chemical Substances | Antineoplastic Agents ; Carboplatin (BG3F62OND5) ; Membrane Proteins ; TMEM205 protein, human ; L-2663 | |||||
| Language | English | |||||
| Publishing date | 2021-10-30 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 801461-9 | |||||
| ISSN | 1095-6859 ; 0090-8258 | |||||
| ISSN (online) | 1095-6859 | |||||
| ISSN | 0090-8258 | |||||
| DOI | 10.1016/j.ygyno.2021.10.076 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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