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A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells

Oncogene volume 28, pages 2556–2568 (2009)Cite this article

Abstract

Thiol reactive cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), induced a novel, nonapoptotic and microtubule-associated protein 1 light chain 3 (MAP1 LC3) dependent but nonautophagic form of cell death in colon, breast and prostate cancer cell lines, characterized by extensive cytoplasmic vacuolation with dilatation of endoplasmic reticulum (ER). Disruption of sulfhydryl homeostasis, which resulted in ER stress, accumulation of ubiquitinated proteins and subsequent ER dilation, contributed to peroxisome proliferator-activated receptor γ (PPARγ)-independent cell death by 15d-PGJ2. Absence of intracellular organelles in these vacuoles, shown by electron microscopy and unique fragmentation of lamin B, suggested this form of cell death to be different from autophagy and apoptosis. Cell death induced by 15d-PGJ2 is prevented by cycloheximide and actinomycin D, suggesting a requirement of new protein synthesis for death with cytoplasmic vacuolation. Here, we report for the first time that upregulation and processing of autophagy marker LC3 is an important event in nonautophagic cytoplasmic vacuolation and cell death. Notably, knockdown of LC3 conferred significant protection against 15d-PGJ2-induced cytoplasmic vacuolation and cell death, suggesting a novel role of LC3 in a death process other than autophagy.

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Acknowledgements

We thank Dr Tamotsu Yoshimori of Osaka University, Japan, for LC3 antibody and GFP-LC3 construct and Drs Anthony J Valente and Robert A Clark of UTHSCSA, TX, for Calreticulin antibody. This work was supported by National Institutes of Health grant DK54472 and Morrison Trust Grant to PS and National Institutes of Health grant DK37139 to MAV.

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  1. R Kar: Graduate of Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

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  1. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    R Kar, P K Singha, M A Venkatachalam & P Saikumar

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Correspondence to P Saikumar.

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Kar, R., Singha, P., Venkatachalam, M. et al. A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells. Oncogene 28, 2556–2568 (2009). https://doi.org/10.1038/onc.2009.118

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