LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance

Aggelou, Helen; Chadla, Panagiota; Nikou, Sofia; Karteri, Sofia; Maroulis, Ioannis; Kalofonos, Haralabos; Papadaki, Helen; Bravou, Vasiliki

doi:10.1007/s00428-018-2298-0

Cited by 37 publications

(27 citation statements)

References 49 publications

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“…SSH1-CDK13, SSH1-CDK19, SSH2-EPHB2 were identified with high significance. Slingshot phosphatases have been previously implicated in cancer progression [75,76] and have been known to mediate caspase-modulated actin polymerization towards bacterial clearance upon Legionella infection [77]. In our analysis, Slingshot phosphatase members SSH1, SSH2 were found to be downregulated exclusively in human DCs, while SSH3 was downregulated in both human DCs and MOs.…”

Section: Discussionmentioning

confidence: 55%

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Subbannayya

Pinto

Bösl

et al. 2019

Preprint

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Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focused on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSPmediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study has the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

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Section: Discussionmentioning

confidence: 55%

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Subbannayya

Pinto

Bösl

et al. 2019

Preprint

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“…Cofilin phosphoregulation by SSH-1 is a pivotal factor of actin cytoskeletal remodeling and involving in cancerous cells migration and metastasis [20]. Aggelou et al [9] discovered that LIM kinases 1, LIM kinases 2 and SSH-1 were regulators of actin dynamics cofilin and contributed to colorectal cancer progression and chemoresistance to 5-fluorouracil. These cytokines were also associated with epithelial-mesenchyma transformation (EMT) markers, such as downregulation of E-cadherin and positive expression of ZEB.…”

Section: Discussionmentioning

confidence: 99%

“…SSH-1 likely be a critical factor for stimulus-induced actin remodeling and vascular smooth muscle cell migration. SSH-1 has been found overexpression in various cancers, including pancreatic cancer [7], gastric cancer [8], colorectal cancer [9], etc. The expression of SSH-1 usually predicts a poor prognosis and survival in patients [10].…”

Section: Introductionmentioning

confidence: 99%

Slingshot homolog-1 expression is a poor prognostic factor of pT1 bladder urothelial carcinoma after transurethral resection

Luo

Liu

et al. 2020

World J Urol

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Objective Slingshot homolog-1 (SSH-1) shows an important role in the occurrence and development in various tumors. While, the expression and prognostic implications of SSH-1 in bladder urothelial carcinoma (UC) remain unclear and thus were addressed in this study. Methods Immunohistochemistry (IHC) was performed on tissue microarrays composed of 624 bladder UC specimens after transurethral resection of bladder tumor (TUR-BT) to detect SSH-1 expression. The clinic-pathological features were compared between SSH-1(+) and SSH-1(−) subgroups. The Kaplan-Meier curve with log-rank test and univariate/multivariate Cox regression model with stepwise backward elimination methods were performed for survival analyses. Results In this study, 359 (57.53%) specimens were detected with SSH-1 expression. SSH-1 positivity was significantly associated with higher pathological grade (p = 0.020), lymphovascular invasion (p = 0.006), tumor recurrence (p < 0.001) and progression (p < 0.001) in bladder UC. Besides, SSH-1 positivity predicted a shorter overall survival (OS, p = 0.024), recurrence-free survival (RFS, p < 0.001), progression-free survival (PFS, p = 0.002) and cancer-specific survival (CSS, p = 0.047). Multivariate Cox proportional hazard analysis showed that tumor size (p = 0.007), lymphovascular invasion (p = 0.003), recurrence (p < 0.001), progression (p < 0.001) and SSH-1 expression (p = 0.015) were predictors of poor prognosis in bladder UC patients. Conclusions SSH-1 expression was associated with undesirable clinic-pathological characteristics and poor post-operative prognosis in bladder UC patients. SSH-1 might play an important role in bladder UC and serve as a promising predictor of oncological outcomes in patients with bladder UC.

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“…The degree of Rac signaling plays a crucial role in the balance between differentiation and proliferation; cellular Rac1 is indispensable for differentiation (35), and RhoA/ROCK signaling plays an important role in differentiation induction (36). The activation of Rho and Rac1 can phosphorylate the kinase ROCK and activate LIMK1, as Rac can activate LIMK1, which induces cofilin 1 phosphorylation at Ser3 and thus regulates the actin cytoskeleton; this process indicates the formation of the Rac1-ROCK1/LIMK1-cofilin signaling pathway by regulating tumor cell migration and invasion (37,38). The inhibition of the ROCK/PTEN pathway and cofilin-1 expression is involved in the induction of cancer cell apoptosis (39).…”

Section: Groupmentioning

confidence: 99%

Diallyl disulfide induces downregulation and inactivation of cofilin�1 differentiation via the Rac1/ROCK1/LIMK1 pathway in leukemia cells

Ling

Lei

et al. 2020

Int J Oncol

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Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)-induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL-60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL-60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho-associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL-60 cells, while 8 µM DADS enhanced the effects of the Rac1-ROCK1-LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL-60 cells. These results suggest that the anticancer function of DADS on HL-60 leukemia cells is regulated by the Rac1-ROCK1-LIMK1-cofilin 1 pathway, indicating that DADS could be a promising anti-leukemia therapeutic compound.

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LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance

Cited by 37 publications

References 49 publications

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Slingshot homolog-1 expression is a poor prognostic factor of pT1 bladder urothelial carcinoma after transurethral resection

Diallyl disulfide induces downregulation and inactivation of cofilin�1 differentiation via the Rac1/ROCK1/LIMK1 pathway in leukemia cells

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