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Apoptosis

, Volume 23, Issue 1, pp 54–64 | Cite as

Caspase cleavage of Mcl-1 impairs its anti-apoptotic activity and proteasomal degradation in non-small lung cancer cells

  • Ting Wang
  • Zhiwei Yang
  • Yimeng Zhang
  • Xiang Zhang
  • Lei Wang
  • Shengli Zhang
  • Lintao Jia
Original Paper

Abstract

Global cleavage of cellular proteins by activated caspases is a hallmark of apoptosis, which causes biochemical collapse of the cell. Recent studies suggest that, rather than completely destroying a protein, caspase cleavage can confer novel characteristics or functions. In this respect, the post-caspase role of Bcl-2 family proteins remains uncharacterized. Here, we showed that Mcl-1, a pro-survival member of the Bcl-2 family, was cleaved by caspase-3 in non-small cell lung cancer (NSCLC) cells undergoing chemotherapeutic agent-triggered apoptosis. Caspase cleavage partially impaired the anti-apoptotic activity of Mcl-1 by reducing its mitochondrial localization and impeding its association with the permeability transition pore-forming protein Bak. However, the stability of cleaved Mcl-1 was markedly enhanced because it was more refractory to ubiquitination-dependent proteasomal degradation, thereby improving cell viability to a greater extent than full-length Mcl-1 when transiently expressed in NSCLC cells. These findings shed new light on the role of Mcl-1 in apoptosis and suggest potential novel targets for optimizing the tumoricidal capacity of chemotherapy.

Keywords

Mcl-1 Chemotherapy Lung cancer Bak Proteasomal degradation 

Abbreviations

Mcl-1

Myeloid cell leukemia 1

BH

Bcl-2 homology

Bax

Bcl-2-associated protein X

NSCLC

Non-small cell lung cancer

PT

Permeability transition

PARP

Poly ADP-ribose polymerase

CHX

Cyclohexane

CCK-8

Cell Counting Kit-8

PI

Propidium iodide

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81472631 and 31200429).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10495_2017_1436_MOESM1_ESM.tif (98 kb)
Supplementary Figure 1. Survival of lung cancer patients (Total) and those receiving routine chemotherapy as grouped by Mcl-1 expression levels. (TIF 98 KB)
10495_2017_1436_MOESM2_ESM.tif (57 kb)
Supplementary Figure 2. Western blot analysis of cells after treatment with CP (20 μmol/L) for the indicated times. (TIF 57 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular BiologyFourth Military Medical UniversityXi’anChina
  2. 2.Department of Applied PhysicsXi’an Jiaotong UniversityXi’anChina

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