Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for n...
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/1967 |
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| author | Naoya Hirata Shigeru Yamada Shota Yanagida Atsushi Ono Yukuto Yasuhiko Motohiro Nishida Yasunari Kanda |
| author_facet | Naoya Hirata Shigeru Yamada Shota Yanagida Atsushi Ono Yukuto Yasuhiko Motohiro Nishida Yasunari Kanda |
| author_sort | Naoya Hirata |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca<sup>2+</sup>), and the increase in Ca<sup>2+</sup> was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca<sup>2+</sup>-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC. |
| first_indexed | 2024-03-09T21:46:22Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:46:22Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c61255b8c6084c14b93454602dc6a8842023-11-23T20:17:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234196710.3390/ijms23041967Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast CancerNaoya Hirata0Shigeru Yamada1Shota Yanagida2Atsushi Ono3Yukuto Yasuhiko4Motohiro Nishida5Yasunari Kanda6Division of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, JapanDivision of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, JapanDivision of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, JapanDivision of Pharmaceutical Sciences, Graduated School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, JapanDivision of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanDivision of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, JapanTriple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca<sup>2+</sup>), and the increase in Ca<sup>2+</sup> was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca<sup>2+</sup>-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC.https://www.mdpi.com/1422-0067/23/4/1967lysophosphatidic acidcancer stem cellstransient receptor potential cation channel subfamily C member 3nuclear factor of activated T cellstriple-negative breast cancer |
| spellingShingle | Naoya Hirata Shigeru Yamada Shota Yanagida Atsushi Ono Yukuto Yasuhiko Motohiro Nishida Yasunari Kanda Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer International Journal of Molecular Sciences lysophosphatidic acid cancer stem cells transient receptor potential cation channel subfamily C member 3 nuclear factor of activated T cells triple-negative breast cancer |
| title | Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer |
| title_full | Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer |
| title_fullStr | Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer |
| title_full_unstemmed | Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer |
| title_short | Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer |
| title_sort | lysophosphatidic acid promotes the expansion of cancer stem cells via trpc3 channels in triple negative breast cancer |
| topic | lysophosphatidic acid cancer stem cells transient receptor potential cation channel subfamily C member 3 nuclear factor of activated T cells triple-negative breast cancer |
| url | https://www.mdpi.com/1422-0067/23/4/1967 |
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