Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells

Siqueira, Raoni Pais; Caetano, Mônica Maria Magalhães; Souza, Luciana Ângelo de; Passos, Patrícia Maria Siqueira dos; Simaroli, Natália B.; Barros, Marcus Vinícius de Andrade; Souza, Ana Paula Martins de; Oliveira, Leandro Licursi de; Silva-Júnior, Abelardo; Fietto, Juliana Lopes Rangel; Teixeira, Róbson Ricardo; Teixeira, Felipe Roberti; Bressan, Gustavo Costa

doi:10.1016/j.tiv.2020.104777

Cited by 13 publications

(7 citation statements)

References 34 publications

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“…For example, rather unexpectedly pharmacological inhibition of SRPK1 did not interfere with AKT signalling in endometrial cancer cells, with the authors suggesting a feedback loop may be present within the pathway [31]. A similar finding was illustrated in T-ALL cell lines where combined AKT/SRPK1 inhibition was required to impede AKT/PI3K signalling [74]. In contrast SRPK1 inhibition alone is sufficient to interfere with AKT signalling in many other cancers [25,32,37,67,68,70].…”

Section: Discussionmentioning

confidence: 85%

“…Interestingly SRPK1 inhibition alone was not found to effect cell apoptosis in this study, rather synergistic treatment alongside an AKT inhibitor was found to have a significant effect on apoptosis. This suggests the likely presence of a regulatory feedback loop within the signalling cascade in this cell type [74].…”

Section: Leukaemiamentioning

confidence: 91%

“…Five studies examined the role of SRPK1 in the development of various luekaemias [70][71][72][73][74]. Siqueira et al, found SRPK1 to be overexpressed in myeloid and lymphoid leukaemia cell lines.…”

Section: Leukaemiamentioning

confidence: 99%

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Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis

et al. 2022

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Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1’s relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.

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Section: Discussionmentioning

confidence: 85%

Section: Leukaemiamentioning

confidence: 91%

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Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis

et al. 2022

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“…It was shown that inhibition of the protein kinase SRPK1 reduces phosphorylation of the splicing factors SRSF1 and SRSF2, resulting in significant splicing dysregulation in AML cells. Importantly, the SRPK1-dependent phosphorylation of splicing factor SRSF1 in Y19 was defined as a specific diagnostic marker of some AML patients [ 318 , 319 , 320 ]. Additionally, the altered splicing was detected in pancreatic ductal adenocarcinoma cells due to enhanced phosphorylation of splicing factor SRSF5 in S250 [ 321 ].…”

Section: Defects In Splicing and Cancermentioning

confidence: 99%

Regulation of Pre-mRNA Splicing: Indispensable Role of Post-Translational Modifications of Splicing Factors

Kretova

Selicky

Cipakova

et al. 2023

Life

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Pre-mRNA splicing is a process used by eukaryotic cells to generate messenger RNAs that can be translated into proteins. During splicing, the non-coding regions of the RNAs (introns) are removed from pre-mRNAs and the coding regions (exons) are joined together, resulting in mature mRNAs. The particular steps of splicing are executed by the multimegadalton complex called a spliceosome. This complex is composed of small nuclear ribonucleoproteins, various splicing factors, and other regulatory and auxiliary proteins. In recent years, various post-translational modifications of splicing factors have been shown to contribute significantly to regulation of processes involved in pre-mRNA splicing. In this review, we provide an overview of the most important post-translational modifications of splicing factors that are indispensable for their normal function during pre-mRNA splicing (i.e., phosphorylation, acetylation, methylation, ubiquitination and sumoylation). Moreover, we also discuss how the defects in regulation of splicing factors are related to the development of cancer.

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“…Esses achados estão de acordo com os de outros estudos, onde compostos sintetizados inspirados no SRPIN340 também mostraram citotoxicidade significativa contra células de glioblastoma, melanoma e leucemia (MOREIRA et al, 2018;SOUSA et al, 2021;SIQUEIRA et al, 2017). Essa maior citotoxicidade dos compostos análogos a SRPIN340 pode ter relação com a já relatada baixa potência de SRPIN340, conforme vista em estudos anteriores (GAMMONS et al, 2014;SIQUEIRA et al, 2020). Além disso, sugere-se que os compostos análogos podem ter uma maior ação inibitória de SRPK, já que esta transferase está envolvida na resistência citotóxica de células tumorais a terapias anticâncer através da evasão da apoptose celular, além de também contribuir com a viabilidade celular (DONG et al, 2022;HUANG et al, 2021;ODUNSI et al, 2012) A expressão elevada e atividade de SRPK1 é causa de desfechos não favoráveis em câncer de mama, como metástases, mau prognóstico clínico, fuga da apoptose celular, resistência a tratamentos anticâncer, recorrência da doença, além de menor sobrevida (LI et al, 2014;LIN et al, 2014;MALVI et al, 2020;van ROOSMALEN et al, 2015;WANG et al, 2020).…”

Section: Discussionunclassified

Efeito do inibidor de serine arginine protein kinases (SRPKS) SRPIN340 e derivados em células murinas de câncer de mama metastático

Paiva¹

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Globalmente, o câncer de mama é o câncer mais comum e a segunda principal causa de mortalidade e morbidade em mulheres. No Brasil, dados INCA mostram que esse câncer é o mais incidente no público feminino, além de ser a principal causa de morte por câncer neste gênero. Diversos fatores são responsáveis pela alta taxa de mortalidade do câncer de mama, onde a metástase para órgãos vitais é identificada como o principal dentre eles. Um crescente número de evidências tem associado o splicing alternativo disfuncional de genes e as atividades e/ou expressões alteradas de moléculas chaves deste processo a fenótipos metastáticos e carcinogênicos. Nesse sentido, as serine/arginine protein kinases (SRPKs), que atuam fosforilando fatores de splicing da família SR, têm sido encontradas superexpressas em diferentes tipos de câncer, incluindo o câncer de mama metastático. Neste estudo foi investigada a atividade biológica de um conjunto de novas moléculas derivadas de um inibidor de SRPKs (SRPIN340) sobre células de câncer de mama e de outros tumores cuja expressão de SRPKs já foi demonstrada. A substância MR48 foi identificada por apresentar atividade citotóxica nos ensaios de viabilidade e por apresentar efeitos antimetastáticos em linhagem de célula de câncer de mama metastático 4T1, este composto também prejudicou a atividade de SRPK1 intracelularmente. Adicionalmente, foi também realizado estudo piloto visando estabelecer um modelo murino de câncer de mama metastático baseado na inoculação da linhagem 4T1 em camundongos. Para tal, animais BALB/c fêmeas foram inoculadas com suspensões das células 4T1 em diferentes densidades na 4 ª glândula mamária. O curso da doença foi monitorado, no entanto, os animais não foram capazes de gerar tumores de forma satisfatória. Novos ensaios devem ser realizados visando otimizar o estabelecimento deste modelo de câncer de mama. Em suma, este trabalho identificou uma molécula promissora que deve ser melhor avaliada em futuros estudos in vitro e in vivo. Palavras-chave: Serine Arginine Protein kinases. Células murinas. Câncer de mama metastático.

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Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells

Cited by 13 publications

References 34 publications

Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis

Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis

Regulation of Pre-mRNA Splicing: Indispensable Role of Post-Translational Modifications of Splicing Factors

Efeito do inibidor de serine arginine protein kinases (SRPKS) SRPIN340 e derivados em células murinas de câncer de mama metastático

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