Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

Fu, Meili; Shi, Wenhong; Li, Zhengling; Liu, Haiyan

doi:10.1016/j.bbrc.2016.04.147

Cited by 31 publications

(22 citation statements)

References 25 publications

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“…To further this hypothesis, shRNA method was applied to stably knockdown cyclophilin-D, the key component of mPTP. A total of three non-overlapping cyclophilin-D shRNAs (from Dr. Xu [ 29 ]) were applied: cyclophilin-D shRNA-1/2/3. All three of them efficiently downregulated cyclophilin-D in SCC-9 cells (Figure 5E ).…”

Section: Resultsmentioning

confidence: 99%

“…As described previously [ 29 , 35 ], JC-10 dye assay (Invitrogen) was performed to reflect mitochondrial membrane potential (MMP) reduction. Briefly, following the treatment, cells were stained with JC-10 (5 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

“…The three verified lentiviral cyclophilin-D shRNAs (with non-overlapping sequences) and the nonsense scramble shRNA were gifts from Dr. Xu [ 29 ]. The lentiviral shRNA was added directly to cells for 12h.…”

Section: Methodsmentioning

confidence: 99%

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GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway

Xie

Ding

et al. 2017

Oncotarget

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This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release. Reversely, mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid) or cyclophilin-D shRNA dramatically alleviated GSK1059615-induced SCC-9 cell death. Further studies demonstrated that GSK1059615 i.p. injection suppressed SCC-9 tumor growth in nude mice, which was compromised with co-administration with cyclosporin A. Thus, targeting PI3K-AKT-mTOR pathway by GSK1059615 possibly provokes programmed necrosis pathway to kill HNSCC cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway

Xie

Ding

et al. 2017

Oncotarget

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“…Hepatocellular carcinoma (HCC), one of the most deadly cancers worldwide, accounts for the majority of primary liver cancer cases (1). The overexpression of histone deacetylases (HDACs) plays an important role in almost all cancerous behaviors of HCC, including cancer initiation, progression and chemotherapy-resistance (2). A number of HDAC inhibitors, such as vorinostat and trichostatin A, have been tested to treat HCC both in preclinical models and clinical trials (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

BAY 87‑2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK‑3β activation

Rao

Zhang

et al. 2019

Exp Ther Med

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Hepatocellular carcinoma (HCC) is associated with some of the highest cancer-associated mortality rates. Histone deacetylase (HDAC) inhibitors anti-HCC activities have been shown to promote Snail-induced metastasis. In the present study, it was shown that BAY 87-2243, a hypoxia-inducible transcription factor-1α inhibitor, could enhance the anti-HCC effects of HDAC inhibitors, including trichostatin A and vorinostat. In addition, BAY 87-2243 plus HDAC inhibitors exhibited synergistic cytotoxicity and induced significant cell death in Hep3B cells. Additionally, BAY 87-2243 combined with HDAC inhibitors-treated Hep3B cells formed fewer and smaller colonies as compared with either the control or single agent-treated cells. Furthermore, glycogen synthase kinase-3β might be involved in the enhanced cell death induced by BAY 87-2243 plus HDAC inhibitors. The present data also indicated that BAY 87-2243 combined with HDAC inhibitors could suppress the migration of Hep3B cells, and BAY 87-2243 could reverse the HDAC inhibitor-induced Snail activation in Hep3B cells. In conclusion, BAY 87-2243 combined with HDAC inhibitors might be an attractive chemotherapy strategy for HCC therapy.

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“…Therefore, the impairment of mitochondrial function is proposed to play a causative role in tumor formation and development. 8,9 Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a multiple-function transcription coactivator that regulates the activity of multiple nuclear receptors and transcription factors involved in mitochondrial biogenesis, [10][11][12] and it also regulates oxidative metabolism in various tissues by coactivating other nuclear receptors and transcriptional factors. 13 PGC-1α also regulates the expression of many genes that code for mitochondrial proteins.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma

Zhang

et al. 2017

Tumour Biol.

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Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in the formation and development of hepatocellular carcinoma and that peroxisome proliferator-activated receptor gamma coactivator-1 alpha may be a potential therapeutic target for hepatocellular carcinoma.

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Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

Cited by 31 publications

References 25 publications

GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway

GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway

BAY 87‑2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK‑3β activation

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma

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