A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells.
Thiol reactive cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)-prostaglandin J(2) (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 gamma (PPARgamma)-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.
Kar
R
R
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Singha
P K
PK
Venkatachalam
M A
MA
Saikumar
P
P
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy; D000071190:Autophagy-Related Protein 8 Family; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation; D014617:Vacuoles / Q000187:drug effects*
C477819:15-deoxyprostaglandin J2; D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D000071190:Autophagy-Related Protein 8 Family; C498698:GABARAPL2 protein, human; C477012:MAP1LC3A protein, human; C502070:MAP1LC3B protein, human; C502071:MAP1LC3C protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D015230:Prostaglandin D2