Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition

Riccardo Cazzoli; Francesco Romeo; Isabella Pallavicini; Sebastiano Peri; Mauro Romanenghi; Juan Alberto Pérez-Valencia; Eman Hagag; Filippo Ferrucci; Mohamed Elgendy; Orazio Vittorio; Salvatore Pece; Marco Foiani; Jukka Westermarck; Saverio Minucci

doi:10.1016/j.celrep.2023.112616

Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition

Riccardo Cazzoli, Francesco Romeo, Isabella Pallavicini, Sebastiano Peri, Mauro Romanenghi, Juan Alberto Pérez-Valencia, Eman Hagag, Filippo Ferrucci, Mohamed Elgendy, Orazio Vittorio, Salvatore Pece, Marco Foiani, Jukka Westermarck, Saverio Minucci^*

^*Corresponding author for this work

Turku Bioscience

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Abstract

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

Original language	English
Article number	112616
Number of pages	15
Journal	Cell Reports
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2023.112616
Publication status	Published - 27 Jun 2023
MoE publication type	A1 Journal article-refereed

Funding

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds. S.M. is funded by AIRC ( IG20-24944 ). J.W. was funded by Sigrid Juselius Foundation. M.E. has received funding from the European Research Council (ERC) under Horizon 2020 research and innovation programme (Onco-Energetics_OFF, grant agreement no. 852761 ) and has received partial support from Czech Science Foundation (project no. 19-22156Y ) and National Institute for Cancer Research (Program EXCELES, ID project no. LX22NPO5102 ). This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds. S.M. is funded by AIRC (IG20-24944). J.W. was funded by Sigrid Juselius Foundation. M.E. has received funding from the European Research Council (ERC) under Horizon 2020 research and innovation programme (Onco-Energetics_OFF, grant agreement no. 852761) and has received partial support from Czech Science Foundation (project no. 19-22156Y) and National Institute for Cancer Research (Program EXCELES, ID project no. LX22NPO5102). We would like to thank the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, particularly Giulio Draetta and Christopher Vellano, for providing IACS-010759; Isabella Dalle Donne and Graziano Colombo (University of Milan) for experimental support and comments; and Bruno Amati, Giulio Donati (European Institute of Oncology, Milan), Claudio Vernieri (IFOM and National Cancer Institute, Milan), and Marco Giorgio (University of Padua) for their useful insights, comments, and scientific discussion. Graphical abstract created with BioRender.com, Conceptualization, R.C. and S.M.; methodology, R.C. F.R. and S.M.; investigation, R.C. F.R. I.P. S. Peri, M.R. J.P.-V. E.H. and F.F.; writing – original draft, R.C. and S.M.; writing – review & editing, M.E. O.V. S. Pece, M.F. and J.W.; funding acquisition, S.M. and M.E.; supervision, S.M. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

Funders	Funder number
National Cancer Institute
The University of Texas MD Anderson Cancer Center
National Cancer Research Institute	LX22NPO5102
Istituto Europeo di Oncologia
European Research Council
Czech Science Foundation	19-22156Y
Ministry of Health
Università degli Studi di Padova
Associazione Italiana per la Ricerca sul Cancro	IG20-24944
Sigrid Jusélius Foundation
Horizon 2020	852761

Keywords

cancer
chaperone-mediated autophagy
CIP2A
CP: Cancer
CP: Molecular biology
fasting
glycolysis
metabolism
OXPHOS
PP2A

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10.1016/j.celrep.2023.112616

PIIS2211124723006277Final published version, 3.98 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi-fe202402136926

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Cazzoli, R., Romeo, F., Pallavicini, I., Peri, S., Romanenghi, M., Pérez-Valencia, J. A., Hagag, E., Ferrucci, F., Elgendy, M., Vittorio, O., Pece, S., Foiani, M., Westermarck, J., & Minucci, S. (2023). Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition. Cell Reports, 42(6), Article 112616. https://doi.org/10.1016/j.celrep.2023.112616

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title = "Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition",

abstract = "Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.",

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Cazzoli, R, Romeo, F, Pallavicini, I, Peri, S, Romanenghi, M, Pérez-Valencia, JA, Hagag, E, Ferrucci, F, Elgendy, M, Vittorio, O, Pece, S, Foiani, M, Westermarck, J & Minucci, S 2023, 'Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition', Cell Reports, vol. 42, no. 6, 112616. https://doi.org/10.1016/j.celrep.2023.112616

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T1 - Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition

AU - Cazzoli, Riccardo

AU - Romeo, Francesco

AU - Pallavicini, Isabella

AU - Peri, Sebastiano

AU - Romanenghi, Mauro

AU - Pérez-Valencia, Juan Alberto

AU - Hagag, Eman

AU - Ferrucci, Filippo

AU - Elgendy, Mohamed

AU - Vittorio, Orazio

AU - Pece, Salvatore

AU - Foiani, Marco

AU - Westermarck, Jukka

AU - Minucci, Saverio

PY - 2023/6/27

Y1 - 2023/6/27

N2 - Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

AB - Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

KW - cancer

KW - chaperone-mediated autophagy

KW - CIP2A

KW - CP: Cancer

KW - CP: Molecular biology

KW - fasting

KW - glycolysis

KW - metabolism

KW - OXPHOS

KW - PP2A

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C2 - 37289585

AN - SCOPUS:85161282536

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 112616

ER -

Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition

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