The C/EBPbeta isoform, liver-inhibitory protein (LIP), induces autophagy in breast cancer cell lines

Abstract

Autophagy is a process involving the bulk degradation of cellular components in the cytoplasm via the lysosomal degradation pathway. Autophagy manifests a protective role in stressful conditions such as nutrient or growth factor depletion; however, extensive degradation of regulatory molecules or organelles essential for survival can lead to the demise of the cell, or autophagy-mediated cell death. The role of autophagy in cancer is complex with roles in both tumor suppression and tumor promotion proposed.Here we report that an isoform of the C/EBPbeta transcription factor, liver-enriched inhibitory protein (LIP), induces cell death in human breast cancer cells and stimulates autophagy. Overexpression of LIP is incompatible with cell growth and when cell cycle analysis was performed, a DNA profile of cells undergoing apoptosis was not observed. Instead, LIP expressing cells appeared to have large autophagic vesicles when examined via electron microscopy. Autophagy was further assessed in LIP expressing cells by monitoring the development of acidic vesicular organelles and conversion of LC3 from the cytoplasmic form to the membrane-bound form. Our work shows that C/EBPbeta isoform, LIP, is another member of the group of transcription factors, including E2F1 and p53, which are capable of playing a role in autophagy.

Degradation of polyomavirus JC T-antigen by stress involves the LIP isoform of C/EBP

“…Since LIP has been found to be regulated by the ER stress response program 15 and can regulate stress-triggered processes, 16,17 we examined the effect of ectopically expressed LIP on T-Ag expression levels. As shown in Figure 2A, transfecting increasing amounts LIP expression plasmid into BsB8 cells caused a progressive decline in T-Ag expression.…”

“…14 LIP has been found to be regulated by the stress response program induced by ER stress 15 and LIP regulates stress-triggered cell death 16 and autophagy. 17 In the present study, we examine the effect of C/EBPb LIP on JCV T-Ag.…”

Mechanisms of autophagy and apoptosis: Recent developments in breast cancer cells

“…However, chemical inhibitors of autophagy also prevent the death of cancer cells induced by a variety of agents [17] . This opposite role of autophagy as an executioner of cell death [18][19][20] and, thus, playing a role as a tumor suppressor [11] , could probably be explained by a persistent degradation of components essential for cell survival [4,21] . Therefore, it appears that, in addition to its conventional role in cell survival, autophagy can be also a death-promoter, in particular when the stimulus is too intense, when autophagy is extensive, or under conditions of inhibition of apoptosis.…”

“…Thus, there is a form of cell death, whose main feature is the appearance of abundant autophagic vacuoles in the cytoplasm of dying cells, known as autophagic or type Ⅱ cell death, and several of its characteristics, based mainly on morphological criteria, have been described in recent years [20] . Type Ⅱ cell death would occur because of persistent autophagy with excessive degradation of cell components essential for survival [4,21] , and it is usually accompanied by inhibition of the phosphatidylinositol 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3kinase/Akt/mTOR) signaling pathway [37,38] , which is the main regulator of autophagy, and by increased levels of LC3-Ⅱ [1] , a protein that is recruited to autophagosomes and that, under certain conditions, can be used as a reliable marker for autophagy [39,40] . However, different studies have found that some of the apoptotic cell death features cited above are also associated with an increased autophagy [18,29] .…”

REPA: Applying Pathway Analysis to Genome-Wide Transcription Factor Binding Data

“…REPA's predictions associated 58 TFs with the gene sets identified as differentially expressed in the breast cancer expression profiling study. Out of these 58 TFs, 50 (or 86%) have previously been directly linked to breast cancer; namely, AP2ALPHA [85], AP2GAMMA [85], ATF1 [86], ATF2 [87], ATF3 [88], BAF155 [89], BCL3 [90], BCLAF1 [91], BHLHE40 [92], [93], BRCA1 [94], CBX3 [95], CEBPB [96], CJUN [97], COREST [98], CREB1 [99], E2F4 [100], E2F6 [61], EBF [101], ELF1 [102], ELK1 [103], ETS1 [104], FOXM1 [105], GABP [106], GR [107], HEY1 [108], IKZF1 [109], INI1 [110], KAP1 [111], MAX [112], MBD4 [113], MTA3 [114], MXI1 [115], MYBL2 [116], NFATC1 [117], NFIC [118], NRSF [119], PAX5 [120], PML [121], POL2 [122] RUNX3 [123], SMC3 [124], SP1 [125], SP4 [126], STAT3 [127], STAT5A …”