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Klotho-beta attenuates Rab8a-mediated exosome regulation and promotes prostate cancer progression

Abstract

Tumor-secreted exosomes have a wide range of effects on the growth, metastasis, and drug resistance of cancer cells. However, whether and how the molecular mechanisms that regulate the secretion of exosomes could affect tumor progression remains poorly understood. Klotho beta (KLB) has been reported dysregulated in prostate cancer, but its function remains unknown. Herein, we first determined that KLB was upregulated in prostate cancer and its expression level was positively correlated with prostate cancer malignant phenotype both in vitro and in vivo. Intriguingly, KLB overexpression could impair the release of exosomes and cause the intracellular accumulation of multivesicular bodies (MVBs) in prostate cancer cells. Mechanistically, KLB attenuated exosomes secretion through a Rab8a-dependent pathway. Rab8a was downregulated in KLB overexpressing cells whereas overexpression of Rab8a could rescue the impaired release of exosomes and attenuate the KLB-induced malignant phenotype of prostate cancer both in vitro and in vivo. Taken together, this study has unveiled the tumor-promoting role of KLB mediated by its regulation on exosomes secretion through a Rab8a-dependent mechanism. These findings could be exploited to develop novel theranostic targets for prostate cancer.

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Fig. 1: High expression of KLB is associated with prostate cancer progression.
Fig. 2: KLB is essential for proliferation and migration of prostate cancer cells.
Fig. 3: Activation of FGFR4-mTOR signaling pathway by KLB, which is inhibited by the mTOR inhibitor rapamycin.
Fig. 4: KLB mediates exosomes secretion and the MVBs distribution in prostate cancer cells.
Fig. 5: Reciprocal regulation and interaction of KLB with Rab8a.
Fig. 6: Overexpression of Rab8a attenuates KLB-induced proliferation of prostate cancer cells.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data underlying the study are available on request to the authors.

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Acknowledgements

We thank Xinqiu Guo, Yanhua Zhu, and Mengyu Yan (Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China) for the technical support of TEM.

Funding

This work was supported by grants from Ministry of Science and Technology (2022YFC2702703), Science and Technology Commission of Shanghai Municipality (21ZR1433100), National Natural Science Foundation of China (81773115) and SJTU funding (YG2022ZD016, YG2017MS52).

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TW designed and performed experiments and wrote the paper. YZ and QH participated in writing the paper and the discussion of related experiments. YC and XL performed imaging analysis. JC participated in animal experiments. JS provided clinical samples and information. WX conceived and supervised the project, obtained the funding and proofed the writing.

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Correspondence to Weiliang Xia.

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For investigations on humans, ethics committee approval from School of Biomedical Engineering, Shanghai Jiao Tong University was obtained prior to the research (BME-2017032) and informed written consent of all participants were obtained. All animal studies were performed following the Institutional Ethics Committee of School of Biomedical Engineering, Shanghai Jiao Tong University (BME-2021013).

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Wu, T., Zhang, Y., Han, Q. et al. Klotho-beta attenuates Rab8a-mediated exosome regulation and promotes prostate cancer progression. Oncogene 42, 2801–2815 (2023). https://doi.org/10.1038/s41388-023-02807-2

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