Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis
Lactate and tumor cell-derived extracellular vesicles (TEVs) both contribute to tumor progression. However, it is still unclear whether lactate can accelerate tumor development by directly promoting TEV production. Here, we show that lactate decreases intracellular cAMP levels and subsequent PKA act...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1036543/full |
| _version_ | 1798014603940069376 |
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| author | Man Luo Junqi Zhu Jie Ren Yuxiao Tong Limin Wang Shenglin Ma Shenglin Ma Shenglin Ma Jiaoli Wang Jiaoli Wang Jiaoli Wang Jiaoli Wang |
| author_facet | Man Luo Junqi Zhu Jie Ren Yuxiao Tong Limin Wang Shenglin Ma Shenglin Ma Shenglin Ma Jiaoli Wang Jiaoli Wang Jiaoli Wang Jiaoli Wang |
| author_sort | Man Luo |
| collection | DOAJ |
| description | Lactate and tumor cell-derived extracellular vesicles (TEVs) both contribute to tumor progression. However, it is still unclear whether lactate can accelerate tumor development by directly promoting TEV production. Here, we show that lactate decreases intracellular cAMP levels and subsequent PKA activation via GPR81, which inhibits the PKA-induced ubiquitination of HIF-1α that causes degradation. Then, the HIF-1α-mediated transcription of Rab27a is enhanced, leading to increased TEV release. In this way, lactate promotes lung metastasis by murine melanoma. In addition, we show that serum lactate levels are positively correlated with serum EV levels and Rab27a and HIF-1α protein levels in the tumor tissues of lung cancer patients. Thus, our results reveal a novel mechanism underlying lactate-mediated tumor progression induced by TEVs and provide new strategies for tumor therapy. |
| first_indexed | 2024-04-11T15:20:01Z |
| format | Article |
| id | doaj.art-1fc43eee52b14b6297ec0b52caa759d3 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T15:20:01Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-1fc43eee52b14b6297ec0b52caa759d32022-12-22T04:16:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-12-011210.3389/fonc.2022.10365431036543Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axisMan Luo0Junqi Zhu1Jie Ren2Yuxiao Tong3Limin Wang4Shenglin Ma5Shenglin Ma6Shenglin Ma7Jiaoli Wang8Jiaoli Wang9Jiaoli Wang10Jiaoli Wang11Department of Respiratory Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaThe Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, ChinaThe Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, ChinaThe Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, ChinaDepartment of Respiratory Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Translation Medicine Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang University Cancer Centre, Hangzhou, ChinaDepartment of Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Respiratory Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaThe Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, ChinaDepartment of Translation Medicine Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang University Cancer Centre, Hangzhou, ChinaLactate and tumor cell-derived extracellular vesicles (TEVs) both contribute to tumor progression. However, it is still unclear whether lactate can accelerate tumor development by directly promoting TEV production. Here, we show that lactate decreases intracellular cAMP levels and subsequent PKA activation via GPR81, which inhibits the PKA-induced ubiquitination of HIF-1α that causes degradation. Then, the HIF-1α-mediated transcription of Rab27a is enhanced, leading to increased TEV release. In this way, lactate promotes lung metastasis by murine melanoma. In addition, we show that serum lactate levels are positively correlated with serum EV levels and Rab27a and HIF-1α protein levels in the tumor tissues of lung cancer patients. Thus, our results reveal a novel mechanism underlying lactate-mediated tumor progression induced by TEVs and provide new strategies for tumor therapy.https://www.frontiersin.org/articles/10.3389/fonc.2022.1036543/fulllactateextracellular vesiclestumorGPR81HIF-1α |
| spellingShingle | Man Luo Junqi Zhu Jie Ren Yuxiao Tong Limin Wang Shenglin Ma Shenglin Ma Shenglin Ma Jiaoli Wang Jiaoli Wang Jiaoli Wang Jiaoli Wang Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis Frontiers in Oncology lactate extracellular vesicles tumor GPR81 HIF-1α |
| title | Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis |
| title_full | Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis |
| title_fullStr | Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis |
| title_full_unstemmed | Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis |
| title_short | Lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the GPR81-cAMP-PKA-HIF-1α axis |
| title_sort | lactate increases tumor malignancy by promoting tumor small extracellular vesicles production via the gpr81 camp pka hif 1α axis |
| topic | lactate extracellular vesicles tumor GPR81 HIF-1α |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1036543/full |
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