Cofilin and profilin: partners in cancer aggressiveness

Coumans, Joëlle V. F.; Davey, Rhonda

doi:10.1007/s12551-018-0445-0

Cited by 45 publications

(35 citation statements)

References 154 publications

(187 reference statements)

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“…Additionally, we observed that NRP2 enriched co lin in the detergentinsoluble fraction ( Figure 3G(a)). Co lin regulation and its effects on actin polymerization are responsible for cell motility and metastasis [31]. Indeed, according to our data, NRP2 promoted co lin activity in PNET-associated HUVECs, which resulted in increased actin polymerization, membrane protrusion, and cell migration.…”

Section: Discussionsupporting

confidence: 63%

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Luo

et al. 2020

Preprint

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Background: Angiogenesis is a critical step in the growth of pancreatic neuroendocrine tumors (PNETs) and may be a selective target for PNET therapy. However, PNETs are robustly resistant to current anti-angiogenic therapies that primarily target the VEGFR pathway. Thus, the mechanism of PNET angiogenesis urgently needs to be clarified.Methods: Dataset analysis was used to identify angiogenesis-related genes in PNETs. Immunohistochemistry was performed to determine the relationship among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, wound-healing and tube formation assays were performed to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2-induced angiogenesis was detected by constructing plasmids with mutant variants and performing Western blot, and immunofluorescence assays. A mouse model was used to evaluate the effect of the NRP2 antibody in vivo, and clinical data were collected from patient records to verify the association between NRP2 and patient prognosis.Results: NRP2, a VEGFR2 co-receptor, was positively correlated with vascularity but not with VEGFR2 in PNET tissues. NRP2 promoted the migration of human umbilical vein endothelial cells (HUVECs) cultured in the presence of conditioned medium PNET cells via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymerization by activating the actin-binding protein cofilin. Cofilin phosphatase slingshot-1 (SSH1) was highly expressed in NRP2-activating cofilin, and silencing SSH1 ameliorated NRP2-activated HUVEC migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumor growth. Finally, elevated NRP2 expression was associated with poor prognosis in PNET patients.Conclusion: Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings demonstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET.

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Section: Discussionsupporting

confidence: 63%

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Luo

et al. 2020

Preprint

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“…3 G(a)). Cofilin regulation and its effects on actin polymerization are responsible for cell motility and metastasis [ 31 ]. Indeed, according to our data, NRP2 promoted cofilin activity in PNET-associated HUVECs, which resulted in increased actin polymerization, membrane protrusion, and cell migration.…”

Section: Discussionmentioning

confidence: 99%

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Luo

et al. 2020

Cell Biosci

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Background Angiogenesis is a critical step in the growth of pancreatic neuroendocrine tumors (PNETs) and may be a selective target for PNET therapy. However, PNETs are robustly resistant to current anti-angiogenic therapies that primarily target the VEGFR pathway. Thus, the mechanism of PNET angiogenesis urgently needs to be clarified. Methods Dataset analysis was used to identify angiogenesis-related genes in PNETs. Immunohistochemistry was performed to determine the relationship among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, wound-healing and tube formation assays were performed to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2-induced angiogenesis was detected by constructing plasmids with mutant variants and performing Western blot, and immunofluorescence assays. A mouse model was used to evaluate the effect of the NRP2 antibody in vivo, and clinical data were collected from patient records to verify the association between NRP2 and patient prognosis. Results NRP2, a VEGFR2 co-receptor, was positively correlated with vascularity but not with VEGFR2 in PNET tissues. NRP2 promoted the migration of human umbilical vein endothelial cells (HUVECs) cultured in the presence of conditioned medium PNET cells via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymerization by activating the actin-binding protein cofilin. Cofilin phosphatase slingshot-1 (SSH1) was highly expressed in NRP2-activating cofilin, and silencing SSH1 ameliorated NRP2-activated HUVEC migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumor growth. Finally, elevated NRP2 expression was associated with poor prognosis in PNET patients. Conclusion Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings demonstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET.

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“…We also measured an increase in PKCζ/λ (T410/T4033) and cofilin (S3) phosphorylation at the 2-day time point with both single and combined kinase inhibition ( Figure S5). Cofilin is an actin depolymerizing factor known to regulate actin dynamics and cell invasion; however, recent studies have established the role of cofilin in NFκB nuclear translocation [31,32]. The atypical protein kinase C member PKCζ is involved in several survival pathways that are deregulated in cancer and is also involved in the activation of NFκB [33,34].…”

Section: Kinome Response To Combined Met and Mek Inhibition In Nf1-rementioning

confidence: 99%

Kinome Profiling of NF1-Related MPNSTs in Response to Kinase Inhibition and Doxorubicin Reveals Therapeutic Vulnerabilities

Grit

Pridgeon

Essenburg

et al. 2020

Genes

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Neurofibromatosis Type 1 (NF1)-related Malignant Peripheral Nerve Sheath Tumors (MPNST) are highly resistant sarcomas that account for significant mortality. The mechanisms of therapy resistance are not well-understood in MPNSTs, particularly with respect to kinase inhibition strategies. In this study, we aimed to quantify the impact of both the genomic context and targeted therapy on MPNST resistance using reverse phase phosphoproteome array (RPPA) analysis. We treated tumorgrafts from three genetically engineered mouse models using MET (capmatinib) and MEK (trametinib) inhibitors and doxorubicin, and assessed phosphosignaling at 4 h, 2 days, and 21 days. Baseline kinase signaling in our mouse models recapitulated an MET-addicted state (NF1-MET), P53 mutation (NF1-P53), and HGF overexpression (NF1). Following perturbation with the drug, we observed broad and redundant kinome adaptations that extended well beyond canonical RAS/ERK or PI3K/AKT/mTOR signaling. MET and MEK inhibition were both associated with an initial inflammatory response mediated by kinases in the JAK/STAT pathway and NFkB. Growth signaling predominated at the 2-day and 21-day time points as a result of broad RTK and intracellular kinase activation. Interestingly, AXL and NFkB were strongly activated at the 2-day and 21-day time points, and tightly correlated, regardless of the treatment type or genomic context. The degree of kinome adaptation observed in innately resistant tumors was significantly less than the surviving fractions of responsive tumors that exhibited a latency period before reinitiating growth. Lastly, doxorubicin resistance was associated with kinome adaptations that strongly favored growth and survival signaling. These observations confirm that MPNSTs are capable of profound signaling plasticity in the face of kinase inhibition or DNA damaging agent administration. It is possible that by targeting AXL or NFkB, therapy resistance can be mitigated.

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Cofilin and profilin: partners in cancer aggressiveness

Cited by 45 publications

References 154 publications

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

Kinome Profiling of NF1-Related MPNSTs in Response to Kinase Inhibition and Doxorubicin Reveals Therapeutic Vulnerabilities

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