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Nutrient Deprivation Promotes MCL-1 Degradation in an Autophagy-Independent Manner

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Abstract

The antiapoptotic protein Mcl-1, which is an attractive target for cancer treatment, is degraded under nutrient deprivation conditions in different types of cancer. This process sensitizes cancer cells to chemotherapy. It has been found that nutrient deprivation leads to suppression of Mcl-1 synthesis; however, the mechanisms of Mcl-1 degradation under such conditions remain to be elucidated. In this study, we have investigated the contribution of autophagy and proteasomal degradation to the regulation of the level of Mcl-1 protein under nutrient deprivation conditions. We found that these circumstances cause a decrease in the level of Mcl-1 in cancer cells in a macroautophagy-independent manner via proteasomal degradation.

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Abbreviations

Atg proteins:

proteins encoded by autophagy-related genes

Bcl-2:

B-cell leukemia/lymphoma-2 protein

ECL:

enhanced chemiluminescent substrate

ERK:

extracellular signal-regulated kinase

FACS:

fluorescence activated cell sorting

FITC:

fluorescein isothiocyanate

GAPDH:

glyceraldehyde-3-phosphate-dehydrogenase

HBSS:

Hank’s Balanced Salt Solution

MAPK:

mitogen-activated protein kinase

Mcl-1:

myeloid cell leukemia-1 protein

mTORC1:

mammalian target of rapamycin complex 1

ND:

nutrient deprivation

PARP:

poly (ADP-ribose)-polymerase

PCD:

programmed cell death

PI:

propidium iodide

PI3K:

phosphatidylinositol 3-kinase

PBS:

phosphate buffered saline

ROS:

reactive oxygen species

SD:

serum deprivation

Ub:

ubiquitin

USP9X:

ubiquitin-specific peptidase 9, X-linked

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Funding

This work was supported by the Russian Science Foundation (project no. 19-15-00125). The work in the authors’ laboratories is also supported by the Russian Foundation for Basic Research (projects nos. 18-29-09005, 20-015-00500), and by the Swedish (project no. 190345) and Stockholm (project no. 181301) Cancer Societies.

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Authors and Affiliations

  1. Faculty of Basic Medicine, Lomonosov Moscow State University, 119192, Moscow, Russia

    N. V. Pervushin, V. V. Senichkin, A. A. Kapusta, A. S. Gorbunova, B. Zhivotovsky & G. S. Kopeina

  2. Institute of Environmental Medicine, Karolinska Institute, 17177, Stockholm, Sweden

    V. O. Kaminskyy & B. Zhivotovsky

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  1. N. V. Pervushin
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  2. V. V. Senichkin
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  3. A. A. Kapusta
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  4. A. S. Gorbunova
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  5. V. O. Kaminskyy
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  7. G. S. Kopeina
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Correspondence to G. S. Kopeina.

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The authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

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Pervushin, N.V., Senichkin, V.V., Kapusta, A.A. et al. Nutrient Deprivation Promotes MCL-1 Degradation in an Autophagy-Independent Manner. Biochemistry Moscow 85, 1235–1244 (2020). https://doi.org/10.1134/S0006297920100119

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