AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth

Xia, Yingchen; Zha, Jianhua; Sang, Yonghua; Yin, Hui; Xu, Guoqiu; Zhen, Jie; Zhang, Yan; Yu, Bentong

doi:10.1038/s41419-021-03655-2

Cited by 29 publications

(39 citation statements)

References 76 publications

(53 reference statements)

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“…Recent studies have identified a mitochondria-dependent pathway of programmed necrosis, 39 - 43 . A number of anti-cancer agents could provoke the programmed necrosis cascade, contributing to cancer cell death 44 - 48 . The mitochondrial immunoprecipitation (mito-IP) assay results in Figure 3D showed that SKI-V treatment induced p53-CyPD-adenine nucleotide translocator-1 (ANT1) complexation in the mitochondria of pCCa-1 cells, known as the initial step of programmed necrosis cascade induction 39 , 49 , 50 .…”

Section: Resultsmentioning

confidence: 99%

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

Zhang¹,

Cheng²,

Shi³

et al. 2022

Int. J. Biol. Sci.

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Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo , daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo .

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Section: Resultsmentioning

confidence: 99%

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

Zhang¹,

Cheng²,

Shi³

et al. 2022

Int. J. Biol. Sci.

Self Cite

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“…Inhibition of mTOR can result in apoptosis in NSCLC cells [ 24 – 26 ]. The activities of both caspase-3 and caspase-7 were boosted in pCan1 primary cells treated with CC-115 (100 nM, 24 h) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Considering that CC-115-provoked NSCLC cell death was more dramatic than AZD2014 plus NU7026 combine, we tested other possible mechanisms responsible for CC-115’s actions. A number of anticancer agents, including mTOR inhibitors, can induce oxidative injury and ROS production to exacerbate cancer cell death [ 25 , 26 , 34 , 35 ]. In CC-115 (100 nM, 16 h)-treated pCan1 primary cells, ROS levels were significantly boosted, and the CellROX intensity was robustly augmented (Fig.…”

Section: Resultsmentioning

confidence: 99%

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An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Chen

Zhao

et al. 2022

Cell Death Discov.

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Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.

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“…Other methods , including Western blotting, qRT-PCR, CCK-8, colony formation, EdU staining, Transwell assays, TUNEL staining and other apoptosis-related assays were described in the previous studies 25 , 26 . Same set of protein lysates were always run in parallel “sister” gels to test different proteins.…”

Section: Methodsmentioning

confidence: 99%

HBO1 induces histone acetylation and is important for non-small cell lung cancer cell growth

Chen¹,

Hao²,

Zhang³

et al. 2022

Int. J. Biol. Sci.

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We examined the expression and the potential biological function of HBO1 in non-small cell lung cancer (NSCLC). TCGA and Oncomine databases showed that HBO1 transcripts were elevated in NSCLC. Furthermore, in local NSCLC tumor tissues HBO1 expression was higher than that in matched adjacent lung tissues. In primary and immortalized NSCLC cells, HBO1 shRNA robustly inhibited cell viability, proliferation and migration. Moreover, HBO1 knockout by CRISPR/Cas9 induced significant anti-tumor activity in NSCLC cells. Conversely, ectopic HBO1 overexpression in primary NSCLC cells increased proliferation and migration. H3-H4 histone acetylation and expression of several potential oncogenic genes ( CCR2 , MYLK , VEGFR2 and OCIAD2 ) were significantly decreased in NSCLC cells with HBO1 silencing or knockout. They were however increased after HBO1 overexpression. Intratumoral injection of HBO1 shRNA-expressing adeno-associated virus hindered the growth of A549 cell xenografts and primary NSCLC cell xenografts in nude mice. H3-H4 histone acetylation as well as expression of HBO1 and HBO1-dependent genes were decreased in HBO1-silenced NSCLC xenograft tissues. An HBO1 inhibitor WM-3835 potently inhibited NSCLC cell growth. Together, HBO1 overexpression promotes NSCLC cell growth.

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AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth

Cited by 29 publications

References 76 publications

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

HBO1 induces histone acetylation and is important for non-small cell lung cancer cell growth

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