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1.
Cancer Res ; 82(21): 4044-4057, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36069976

RESUMO

Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2-M arrest and DNA damage. The VRK1-VRK2 synthetic-lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM. SIGNIFICANCE: A paralog synthetic-lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.


Assuntos
Glioblastoma , Humanos , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Vaccinia virus , Fosforilação , Proteínas Serina-Treonina Quinases
2.
Cell Cycle ; 20(1): 65-80, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356791

RESUMO

Palbociclib, a selective CDK4/6 kinase inhibitor, is approved in combination with endocrine therapies for the treatment of advanced estrogen receptor positive (ER+) breast cancer. In pre-clinical cancer models, CDK4/6 inhibitors act primarily as cytostatic agents. In two commonly studied ER+ breast cancer cell lines (MCF7 and T47D), CDK4/6 inhibition drives G1-phase arrest and the acquisition of a senescent-like phenotype, both of which are reversible upon palbociclib withdrawal (incomplete senescence). Here we identify an ER+ breast cancer cell line, CAMA1, in which palbociclib treatment induces irreversible cell cycle arrest and senescence (complete senescence). In stark contrast to T47D and MCF7 cells, mTORC1 activity is not stably suppressed in CAMA1 cells during palbociclib treatment. Importantly, inhibition of mTORC1 signaling either by the mTORC1 inhibitor rapamycin or by knockdown of Raptor, a unique component of mTORC1, during palbociclib treatment of CAMA1 cells blocks the induction of complete senescence. These results indicate that sustained mTORC1 activity promotes complete senescence in ER+ breast cancer cells during CDK4/6 inhibitor-induced cell cycle arrest. Consistent with this mechanism, genetic depletion of TSC2, a negative regulator of mTORC1, in MCF7 cells resulted in sustained mTORC1 activity during palbociclib treatment and evoked a complete senescence response. These findings demonstrate that persistent mTORC1 signaling during palbociclib-induced G1 arrest is a potential liability for ER+ breast cancer cells, and suggest a strategy for novel drug combinations with palbociclib.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Estrogênio/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Transdução de Sinais/efeitos dos fármacos
3.
Anticancer Res ; 38(8): 4435-4441, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061207

RESUMO

BACKGROUND/AIM: GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. MATERIALS AND METHODS: Transgenic mice, 3D cultures and xenografts were used to examine the effect of mutant GATA3 expression on mammary cell proliferation. RESULTS: Mutant GATA3 accelerated tumor growth of ZR751 cell xenografts and promoted precocious lobuloalveolar development in transgenic mouse mammary glands. CONCLUSION: GATA3 mutations, recently observed in breast cancer, encode active transcription factors, which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of ER-positive breast cancer cell lines.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Fator de Transcrição GATA3/genética , Mutação/genética , Animais , Mama/patologia , Linhagem Celular Tumoral , Células Epiteliais/patologia , Epitélio/patologia , Feminino , Humanos , Camundongos , Camundongos Nus , Camundongos Transgênicos/genética , Receptores de Estrogênio/genética , Fatores de Transcrição/genética
4.
Cell Rep ; 19(13): 2665-2680, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28658616

RESUMO

Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic enzyme GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, because of a reduction in intracellular guanine nucleotides. AG2037 treatment provokes both mTORC1 inhibition and robust tumor growth suppression in mice bearing non-small-cell lung cancer (NSCLC) xenografts. These results indicate that alterations in purine nucleotide availability affect mTORC1 activity and suggest that inhibition of mTORC1 contributes to the therapeutic effects of purine biosynthesis inhibitors.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Nucleotídeos de Purina/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Nucleotídeos de Purina/biossíntese
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