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Volume 22
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10.3390/ijms22116033
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Article

V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells

by
Eva Jiménez-Mora
1,
Beatriz Gallego
1,
Sergio Díaz-Gago
1,
Marina Lasa
2,
Pablo Baquero
1 and
Antonio Chiloeches
1,*
1
Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain
2
Departamento de Bioquímica-Instituto de Investigaciones Biomédicas “Alberto Sols”, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(11), 6033; https://doi.org/10.3390/ijms22116033
Submission received: 6 May 2021 / Revised: 31 May 2021 / Accepted: 1 June 2021 / Published: 3 June 2021
(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)
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Abstract

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.
Keywords: V600EBRAF; autophagy; LKB1; AMPK; ULK1; survival; thyroid cancer V600EBRAF; autophagy; LKB1; AMPK; ULK1; survival; thyroid cancer

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MDPI and ACS Style

Jiménez-Mora, E.; Gallego, B.; Díaz-Gago, S.; Lasa, M.; Baquero, P.; Chiloeches, A. V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells. Int. J. Mol. Sci. 2021, 22, 6033. https://doi.org/10.3390/ijms22116033

AMA Style

Jiménez-Mora E, Gallego B, Díaz-Gago S, Lasa M, Baquero P, Chiloeches A. V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells. International Journal of Molecular Sciences. 2021; 22(11):6033. https://doi.org/10.3390/ijms22116033

Chicago/Turabian Style

Jiménez-Mora, Eva, Beatriz Gallego, Sergio Díaz-Gago, Marina Lasa, Pablo Baquero, and Antonio Chiloeches. 2021. "V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells" International Journal of Molecular Sciences 22, no. 11: 6033. https://doi.org/10.3390/ijms22116033

APA Style

Jiménez-Mora, E., Gallego, B., Díaz-Gago, S., Lasa, M., Baquero, P., & Chiloeches, A. (2021). V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells. International Journal of Molecular Sciences, 22(11), 6033. https://doi.org/10.3390/ijms22116033

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