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Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer

Abstract

Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.

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Fig. 1: mtDNA copy number, mtUPR, and mTOR signalling in thyroid cancer.
Fig. 2: mtUPR is closely related to the integrated stress response for mTOR signalling activation.
Fig. 3: Dual mechanism via which MSR maintains mTOR activity.
Fig. 4: Integrated stress response comparison between mtUPR and ER UPR.
Fig. 5: mtDNA depletion affects the integrated stress response from mitochondria and the ER.
Fig. 6: MYC transactivation is a critical regulator of positive feedback loop formation in the MSR.

Data availability

The datasets generated during and/or analysed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

Anti-SESN2 polyclonal antibodies and SESN2 plasmids were provided by Prof. Soo Han Bae (Severance Biomedical Science Institute and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 03722, Seoul, South Korea). We thank Ji Young Kim, Hee Chang Yu, Hoyoung Kim, and Hwa Young Lee for their excellent technical support.

Funding

We received funding from the National Research Foundation of Korea grant, funded by the Korean government NRF-2018R1A2B6004179 and NRF-2021R1H1A2012035 (YSJ); NRF-2020R1A2C1006047 (JL); NRF-2020R1I1A1A01069524 (SP); National Research Foundation of Korea GRL grant NRF-2017K1A1A2013124 (JA); École Polytechnique Fédérale de Lausanne (JA and KS); European Research Council ERC-AdG-787702 (JA); Swiss Cancer Research KFS-4226-08-2017 (KS); and Swiss National Science Foundation, Sinergia CRSII3_160798 (KS).

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Conceptualization: JA, JL, and YSJ; Methodology: WKL, SP, SGL, SJ, GL, DR, KS, and JA; Investigation: WKL, SP, SGL, SJ, GL, and DR; Visualization: WKL, SP, SGL, SJ, and GL; Funding acquisition: KS, JA, JL, and YSJ; Project administration: JL and YSJ; Supervision: KS, JA, JL, and YSJ. Writing – original draft: WKL and SP; Writing – review & editing: WKL, SP, SGL, KS, JA, JL, and YSJ.

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Correspondence to Jandee Lee or Young Suk Jo.

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Doolittle, W.K.L., Park, S., Lee, S.G. et al. Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer. Oncogene 41, 4893–4904 (2022). https://doi.org/10.1038/s41388-022-02484-7

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