GNE-493 inhibits prostate cancer cell growth via Akt-mTOR-dependent and -independent mechanisms

Jin, Lü; Zhang, Wei; Yao, Ming-Yu; Tian, Ye; Xue, Boxin; Tao, Wei

doi:10.1038/s41420-022-00911-y

Cited by 10 publications

(10 citation statements)

References 55 publications

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“…The established PC-3/LNCaP prostate cancer cell lines and the non-transformed RWPE1 prostate epithelial cell line were reported previously [ 16 ]. The primary prostate cancer cells (pCan-1 and pCan-2, derived from two written-informed consent patients) and the prostate epithelial cells were obtained and cultivated as described [ 16 ]. The primary pCan-1 and pCan-2 cells were derived from CRPC patients and were PTEN -null, PI3KCA -positive and androgen receptor -positive.…”

Section: Methodsmentioning

confidence: 99%

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

Jin,

Zhu,

Yao

et al. 2023

Cell Death Dis

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Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.

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Section: Methodsmentioning

confidence: 99%

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

Jin,

Zhu,

Yao

et al. 2023

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Western blotting, real-time quantitative reverse transcription PCR (qRT-PCR), nuclear EdU (5-Ethynyl-2′- deoxyuridine)/DAPI (4′,6-diamidino2-phenylindole) staining (testing cell proliferation), nuclear TUNEL (TdT-mediated dUTP Nick-End Labeling)/DAPI staining, propidium iodide (PI)-flow cytometry (testing cell cycle progression), “Transwell” assays (testing in vitro cell migration) and Caspase-3/−9 activity assays were described in other studies [ 20 , 27 – 30 ]. Figure S1 listed the uncropped blotting images.…”

Section: Methodsmentioning

confidence: 99%

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo

Zhang

et al. 2023

Cell Death Dis

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The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

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“…The constitutively-active mutant Akt1 (caAkt1 S473D) was packaged through lentivirus [ 40 ], which was transduced to cultured KCNAB2-OE NSCLC cells. Stable cells were established with neomycin-mediated selection.…”

Section: Methodsmentioning

confidence: 99%

KCNAB2 overexpression inhibits human non-small-cell lung cancer cell growth in vitro and in vivo

Cheng,

Tang,

Cao

et al. 2023

Cell Death Discov.

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Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. NSCLC patients often have poor prognosis demanding urgent identification of novel biomarkers and potential therapeutic targets. KCNAB2 (regulatory beta subunit2 of voltage-gated potassium channel), encoding aldosterone reductase, plays a pivotal role in regulating potassium channel activity. In this research, we tested the expression of KCNAB2 as well as its potential functions in human NSCLC. Bioinformatics analysis shows that expression of KCNAB2 mRNA is significantly downregulated in human NSCLC, correlating with poor overall survival. In addition, decreased KCNAB2 expression was detected in different NSCLC cell lines and local human NSCLC tissues. Exogenous overexpression of KCNAB2 potently suppressed growth, proliferation and motility of established human NSCLC cells and promoted NSCLC cells apoptosis. In contrast, CRISPR/Cas9-induced KCNAB2 knockout further promoted the malignant biological behaviors of NSCLC cells. Protein chip analysis in the KCNAB2-overexpressed NSCLC cells revealed that KCNAB2 plays a possible role in AKT-mTOR cascade activation. Indeed, AKT-mTOR signaling activation was potently inhibited following KCNAB2 overexpression in NSCLC cells. It was however augmented by KCNAB2 knockout. In vivo, the growth of subcutaneous KCNAB2-overexpressed A549 xenografts was significantly inhibited. Collectively, KCNAB2 could be a novel effective gene for prognosis prediction of NSCLC. Targeting KCNAB2 may lead to the development of advanced therapies.

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GNE-493 inhibits prostate cancer cell growth via Akt-mTOR-dependent and -independent mechanisms

Cited by 10 publications

References 55 publications

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo

KCNAB2 overexpression inhibits human non-small-cell lung cancer cell growth in vitro and in vivo

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