p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

Huang, Shi; Wu, Chun Ying; Wang, Yen Ting; Kao, Jun Kai; Lin, Chi Chen; Chang, Chia‐Che; Mu, Szu Wei; Chen, Yu Yu; Chiu, Husan Wen; Chang, Chuan Hsun; Liang, Shu‐Mei; Chen, Yi Ju; Liu, Luxin; Shieh, Jeng-Jer

doi:10.1016/j.taap.2012.12.016

Cited by 28 publications

(38 citation statements)

References 42 publications

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“…40, 41, 42, 43 In agreement with these reports, we saw a similar effect in several cancer cell lines upon treatment with compound C. On the basis of the data that blocking AMPK α had no effects on compound C-induced apoptosis, we suggest compound C induces apoptosis in an AMPK-independent manner in cancer cells. As compound C induces autophagy through AMPK inhibition-independent mechanisms, 56 it is necessary to address whether the induction of autophagy is involved in apoptosis of cancer cells upon compound C treatment.…”

Section: Discussionsupporting

confidence: 91%

“…40, 41, 42, 43 The present work reveals that compound C represses transcription and initiates apoptosis in cancer cells partially by decreasing the expression of Bcl-2 and Bcl-xl, and by inducing the phosphorylation of eIF2 α .…”

Section: Discussionmentioning

confidence: 56%

“…33, 34, 35, 36, 37, 38, 39 In contrast, it has also been suggested that compound C treatment directly causes apoptosis in some cancer cells, including breast cancer cells and skin cancer cells. 40, 41, 42, 43 …”

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confidence: 99%

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Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

Dai

Zhao

et al. 2013

Cell Death Dis

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Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-β-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2α) on Ser51. Hence, the phosphorylation of eIF2α might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2α on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 56%

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Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

Dai

Zhao

et al. 2013

Cell Death Dis

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“…3A, C and E, compound C efficiently inhibited AMPK activation after IMQ treatment but did not affect IMQ-induced autophagy, i.e., LC3-I to LC3-II conversion, EGFP-LC3 puncta formation or acidic autophagolysosome accumulation. Because high concentrations of compound C have been reported to induce autophagy via an AMPK-independent pathway [20,21], we used an AMPK knockdown strategy to confirm this result. In BCC cells treated with IMQ, the shRNA-mediated knockdown of AMPK had no effect on the IMQ-induced LC3-1 to LC3-II conversion (Fig.…”

Section: Imq-induced Autophagy Is Independent Of Ampkmentioning

confidence: 83%

Imiquimod-induced AMPK activation causes translation attenuation and apoptosis but not autophagy

Wang¹,

Huang²,

Kao³

et al. 2015

Journal of Dermatological Science

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“…Evidence reported that defective mitochondrial could lead to DNA damage, which then would activate ATM. DNA damage signal was transmitted by ATM to downstream targets including p-Chk1 and p-Chk2 which played an important role in cell cycle regulation [48–51]. When autophagy was blocked, damaged mitochondria would release ROS and induce of G0/G1 cell cycle arrest [26, 52], causing oxidation of DNA and resulting in DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

Liu

et al. 2017

PLoS ONE

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Epidermal growth factor receptor (EGFR) is over-expressed in about 50% of Triple negative breast cancers (TNBCs), but EGFR inhibitors have not been effective in treating TNBC patients. Increasing evidence supports that autophagy was related to drug resistance at present. However, the role and the mechanism of autophagy to the treatment of TNBC remain unknown. In the current study, we investigated the effect of autophagy inhibitor to gefitinib (Ge) in TNBC cells in vitro and in nude mice vivo. Our study demonstrated that inhibition of autophagy by 3-Methyladenine or bafilomycin A1 improved Ge’s sensitivity to MDA-MB-231 and MDA-MB-468 cells, as evidence from stronger inhibition of cell vitality and colony formation, higher level of G0/G1 arrest and DNA damage, and these effects were verified in nude mice vivo. Our data showed that the mitochondrial-dependent apoptosis pathway was activated in favor of promoting apoptosis in the therapy of Ge combined autophagy inhibitor, as the elevation of BAX/Bcl-2, Cytochrome C, and CASP3. These results demonstrated that targeting autophagy should be considered as an effective therapeutic strategy to enhance the sensitivity of EGFR inhibitors on TNBC.

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p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

Cited by 28 publications

References 42 publications

Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

Imiquimod-induced AMPK activation causes translation attenuation and apoptosis but not autophagy

Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

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