Rottlerin induces autophagy and apoptotic cell death through a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells: The protective role of autophagy in apoptosis

Song, Kyoungsub; Kim, Jong-Seok; Yun, Eun-Jin; Kim, Young‐Rae; Seo, Kang-Sik; Park, Jihoon; Jung, Yeonjoo; Park, Jong-Il; Kweon, Gi‐Ryang; Yoon, Won‐Sang; Lim, Kyu Hee; Hwang, Byungil

doi:10.4161/auto.6057

Cited by 60 publications

(45 citation statements)

References 42 publications

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“…Activated AMPK in turn inhibits mTOR-dependent signaling, hence activating autophagy (37). A very recent report by Song et al (38) provided evidence that rottlerin induces autophagy through PKC␦-independent pathway in HT1080 cells, further supporting our notion. Equal amounts of cell lysates were subjected to Western analyses with specific antibodies as indicated.…”

Section: Mef/pkc␦supporting

confidence: 76%

Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy

Chen

Lin

Kim

et al. 2008

Journal of Biological Chemistry

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Macroautophagy, a tightly orchestrated intracellular process for bulk degradation of cytoplasmic proteins or organelles, is believed to be essential for cell survival or death in response to stress conditions. Recent observations indicate that autophagy is an adaptive response in cells subjected to prolonged hypoxia. However, the signaling mechanisms that activate autophagy under acute hypoxic stress are not clearly understood. In this study, we show that acute hypoxic stress by treatment with 1% O 2 or desferroxamine, a hypoxia-mimetic agent, of cells renders a rapid induction of LC3-II level changes and green fluorescent protein-LC3 puncta accumulation, hallmarks of autophagic processing, and that this process involves protein kinase C␦ (PKC␦), and occurs prior to the induction of BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3). Interestingly, hypoxic stress leads to a rapid and transient activation of JNK in Pa-4 or mouse embryo fibroblast cells. Acute hypoxic stressinduced changes in LC3-II level and JNK activation are attenuated in Pa-4 cells by dominant negative PKC␦KD or in mouse embryo fibroblast/PKC␦-null cells. Intriguingly, the requirement of PKC␦ is not apparent for starvation-induced autophagy. The importance of PKC␦ in hypoxic stress-induced adaptive responses is further supported by our findings that inhibition of PKC␦-facilitated autophagy by 3-methyladenine or Atg5 knock-out renders a greater prevalence of cell death following prolonged desferroxamine treatment, whereas PKC␦-or JNK1-deficient cells exhibit resistance to extended hypoxic exposure. These results uncover dual roles of PKC␦-dependent signaling in the cell fate determination upon hypoxic exposure.

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Section: Mef/pkc␦supporting

confidence: 76%

Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy

Chen

Lin

Kim

et al. 2008

Journal of Biological Chemistry

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“…Plasmid-mediated overexpression of PKCdelta attenuated MMP depolarization and cell death in rottlerin-treated cells. However, in a study with HT1080 fibrosarcoma cells [19], rottlerin induced apoptosis and also autophagy. There was MMP depolarization, but caspases 3 and 9 were unaffected.…”

Section: Discussionmentioning

confidence: 97%

Protection of human colon epithelial cells against deoxycholate by rottlerin

Longpre

Loo

2008

Apoptosis

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The bile salt, deoxycholate (DOC), can harm cells and cause disease. Hence, there is interest in identifying compounds capable of protecting cells against DOC. In HCT-116 colon epithelial cells, DOC increased generation of reactive oxygen species and caused DNA damage and apoptosis. These effects of DOC were inhibited by rottlerin, which is a phenolic compound of plant origin. In elucidating its mechansim, rottlerin prevented the release of cytochrome c from mitochondria into cytosol, and also prevented the cleavage of caspase-3. Yet, rottlerin by itself markedly decreased mitochondrial membrane potential and increased mitochondrial superoxide production, but this did not result in cytochrome c release or in caspase-3 cleavage. At a higher test concentration, two other phenolic phytochemicals, namely, quercetin and resveratrol, were each able to largely prevent the occurrence of apoptosis in cells exposed to DOC. In contrast, epigallocatechin gallate, curcumin, and genistein were ineffective.

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“…It has been reported that rottlerin is a specific inhibitor of PKC δ (Gschwendt et al, 1994), However, some recent studies showed that rottlerin might not act directly on PKC δ, but instead elicit cellular changes that mimic those caused by the direct inhibition of PKC δ (Gschwendt et al, 1994;Soltoff, 2007;Song et al, 2008;Lim et al, 2009;Park et al, 2010). Therefore, we tested the possibility that rottlerin could enhance IL-1β-induced COX-2 expression in human breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…A representative result is shown; two additional experiments yielded similar results. Song et al, 2008;Lim et al, 2009;Park et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Rottlerin enhances IL-1β-induced COX-2 expression through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells

Park

Kwon

2011

Exp Mol Med

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Cyclooxygenase-2 (COX-2) is an important enzyme in inflammation. In this study, we investigated the underlying molecular mechanism of the synergistic effect of rottlerin on interleukin1β (IL-1β)-induced COX-2 expression in MDA-MB-231 human breast cancer cell line. Treatment with rottlerin enhanced IL-1β-induced COX-2 expression at both the protein and mRNA levels. Combined treatment with rottlerin and IL-1β significantly induced COX-2 expression, at least in part, through the enhancement of COX-2 mRNA stability. In addition, rottlerin and IL-1β treatment drove sustained activation of p38 Mitogen-activated protein kinase (MAPK), which is involved in induced COX-2 expression. Also, a pharmacological inhibitor of p38 MAPK (SB 203580) and transient transfection with inactive p38 MAPK inhibited rottlerin and IL-1β-induced COX-2 upregulation. However, suppression of protein kinase C δ (PKC δ) expression by siRNA or overexpression of dominant-negative PKC δ (DN-PKC-δ) did not abrogate the rottlerin plus IL-1β-induced COX-2 expression. Furthermore, rottlerin also enhanced tumor necrosis factor-α (TNF-α), phorbol myristate acetate (PMA), and lipopolysaccharide (LPS)-induced COX-2 expression. Taken together, our results suggest that rottlerin causes IL-1β-induced COX-2 upregulation through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells.

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Rottlerin induces autophagy and apoptotic cell death through a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells: The protective role of autophagy in apoptosis

Cited by 60 publications

References 42 publications

Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy

Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy

Protection of human colon epithelial cells against deoxycholate by rottlerin

Rottlerin enhances IL-1β-induced COX-2 expression through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells

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