Targeting Lyn regulates Snail family shuttling and inhibits metastasis

Thaper, Daksh; Vahid, Sepideh; Nip, Ka Mun; Moskalev, Igor; Shan, Xianghong; Frees, Sebastian; Roberts, Morgan E.; Ketola, Kirsi; Harder, Kenneth W.; Gregory‐Evans, Cheryl Y.; Bishop, Jennifer; Zoubeidi, Amina

doi:10.1038/onc.2017.5

Cited by 34 publications

(26 citation statements)

References 66 publications

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“…In different tumors affecting humans, aberrant expression levels of Snai1 and Snai2 may affect EMT progression, cell invasion and migration ( 44 , 45 ). Snai1 has been demonstrated to induce hepatocellular carcinoma via enhancement of cell growth ( 46 ), and to accelerate pancreatic tumor growth ( 47 ) and breast cancer development ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Zhang

Zhou

2018

Mol Med Report

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Cervical cancer is a serious malignancy that affects the health of females. In the present study, the association between breast cancer type 1 susceptibility protein/breast cancer type 2 susceptibility protein-containing complex subunit 3 (BRCC3) and cervical cancer was investigated. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine BRCC3 mRNA and protein expression levels in cervical cancer tissues and cells, in addition to the expression levels of proteins associated with the epithelial-mesenchymal transition (EMT) process in HeLa and SiHa cells. Cell Counting Kit-8, Transwell and wound healing assays were performed to determine the cell viability, invasion and migration abilities of cervical cancer cells, respectively. The results of the present study revealed that BRCC3 expression was significantly increased in cervical cancer tissues, which was also revealed to be associated with the clinical stages and pathological grades of cervical cancer exhibited by patients, in addition to the survival time. Furthermore, BRCC3 expression levels were enhanced in HeLa, SiHa and C-33A cervical cancer cells. BRCC3 interference in HeLa and SiHa cells was revealed to suppress cell viability, invasion and migration abilities via upregulation of E-cadherin expression levels and downregulation of Vimentin, matrix metalloproteinase (MMP)-2, MMP-9, snail family transcriptional repressor (Snai)1 and Snai2 expression levels. In conclusion, the expression levels of BRCC3 were revealed to be increased in cervical cancer tissues, which were positively associated with clinical features of cervical cancer. Furthermore, BRCC3 interference inhibited the cell viability, invasion and migration abilities of HeLa and SiHa cells via regulation of EMT progression and expression levels of Snai family members. In addition, the results of the present study suggested that BRCC3 represents an oncogene associated with cervical cancer, and may also represent a novel therapeutic biomarker for the diagnosis, treatment and prognosis of patients with cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Zhang

Zhou

2018

Mol Med Report

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“…Cells were plated at 25,000 per in 12 well plates on circular glass slides in a 12 well plate. Cells were fixed and stained as previously described 47 using antibodies against STAT3 (1:100) and AR (1:100). DAPI was used to visualize nuclei and then the pictures were taken using Zeiss LSM confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide-resistant Prostate Cancer

Thaper

Vahid²,

Kaur³

et al. 2018

Sci Rep

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Most prostate cancer patients will progress to a castration-resistant state (CRPC) after androgen ablation therapy and despite the development of new potent anti-androgens, like enzalutamide (ENZ), which prolong survival in CRPC, ENZ-resistance (ENZR) rapidly occurs. Re-activation of the androgen receptor (AR) is a major mechanism of resistance. Interrogating our in vivo derived ENZR model, we discovered that transcription factor STAT3 not only displayed increased nuclear localization but also bound to and facilitated AR activity. We observed increased STAT3 S727 phosphorylation in ENZR cells, which has been previously reported to facilitate AR binding. Strikingly, ENZR cells were more sensitive to inhibition with STAT3 DNA-binding inhibitor galiellalactone (GPA500) compared to CRPC cells. Treatment with GPA500 suppressed AR activity and significantly reduced expression of Cyclin D1, thus reducing cell cycle progression into S phase and hindering cell proliferation. In vivo, GPA500 reduced tumor volume and serum PSA in ENZR xenografts. Lastly, the combination of ENZ and GPA500 was additive in the inhibition of AR activity and proliferation in LNCaP and CRPC cells, providing rationale for combination therapy. Overall, these results suggest that STAT3 inhibition is a rational therapeutic approach for ENZR prostate cancer, and could be valuable in CRPC in combination with ENZ.

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“…Tornillo et al reported that LynA promotes tumour cell invasion and that a high LynA/LynB isoform ratio is associated with poor prognosis of breast cancer patients 30 . Two previous studies from different groups showed that Lyn mediates EMT 28,29 . Although the authors of these two studies did not mention which contributes to the induction of EMT (whether LynA or LynB), at least one study showed results suggesting that the overexpression of LynA induced EMT 28 .…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies suggested that LynA seems to contribute to the aggressive behaviour of some types of cancer [28][29][30] . Tornillo et al reported that LynA promotes tumour cell invasion and that a high LynA/LynB isoform ratio is associated with poor prognosis of breast cancer patients 30 .…”

Section: Discussionmentioning

confidence: 95%

“…LynA reduction accompanying Csk depletion does not affect epithelial or mesenchymal marker protein levels. LynA was reported to be a mediator of the epithelial-mesenchymal transition (EMT), decreasing and increasing epithelial and mesenchymal marker protein levels, respectively 28,29 . This knowledge led us to hypothesize that LynA reduction accompanying Csk depletion serves as a mechanism to protect cancer cells from undergoing EMT.…”

Section: Kinase Activity Of Sfks Is Required For the Depletion Of Cskmentioning

confidence: 99%

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Depletion of Csk preferentially reduces the protein level of LynA in a Cbl-dependent manner in cancer cells

Kuga

Yamane

Hayashi

et al. 2020

Sci Rep

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there are eight human Src-family tyrosine kinases (SfKs). SfK members c-Src, c-Yes, fyn, and Lyn are expressed in various cancer cells. SfK kinase activity is negatively regulated by csk tyrosine kinase. Reduced activity of csk causes aberrant activation of SfKs, which can be degraded by a compensatory mechanism depending on cbl-family ubiquitin ligases. We herein investigated whether all SfK members are similarly downregulated by cbl-family ubiquitin ligases in cancer cells lacking csk activity. We performed Western blotting of multiple cancer cells knocked down for csk and found that the protein levels of the 56 kDa isoform of Lyn (LynA), 53 kDa isoform of Lyn (LynB), c-Src, and Fyn, but not of c-Yes, were reduced by csk depletion. induction of c-cbl protein levels was also observed in csk-depleted cells. The reduction of LynA accompanying the depletion of Csk was significantly reversed by the knockdown for Cbls, whereas such significant recovery of LynB, c-Src, and Fyn was not observed. These results suggested that LynA is selectively downregulated by cbls in cancer cells lacking csk activity. The Src-family tyrosine kinases (SFKs) are composed of eight members in humans: c-Src, c-Yes, Fyn, Lyn, Lck, Fgr, Hck and Blk 1. c-Src, c-Yes, Fyn and Lyn are widely expressed in a variety of cell types, whereas other members are primarily restricted to specific cell types 2. The redundant expression of multiple members of SFKs is observed in almost all cell types 1. SFKs play important roles in various signalling pathways involved in various cellular events, including survival and proliferation, motility and invasion and angiogenesis 1,3,4. The deregulated activation of SFKs promotes tumorigenesis and cancer progression 4,5. The activity of SFKs has been reported to be associated with poor clinical prognosis of cancer patients 6,7. The kinase activity of SFKs is controlled by their post-translational modifications by phosphorylation. The autophosphorylation of the conserved tyrosine residue in their activation loop changes the protein structure into a fully active conformation 8,9. In contrast, the phosphorylation of another conserved tyrosine residue in the C-terminal negative regulatory tail changes the protein structure into an inactive conformation 8,9. This C-terminal tyrosine is phosphorylated by the Csk or Chk tyrosine kinases 10. The loss of Csk therefore leads to the aberrant activation of SFKs 11,12. The reduced activity of Csk is observed in hepatocellular carcinoma 13. The ubiquitin-proteasome system is another mechanism that down-regulates SFKs 14. The degradation of SFKs by the ubiquitin-proteasome system serves as a mechanism to prevent aberrantly activated SFKs from excessively transducing signals. The ubiquitination-dependent degradation of c-Src and Fyn was observed in mouse embryonic fibroblasts containing a targeted disruption of the Csk gene 15. The inhibition of Csk in bone marrow-derived macrophages led to the ubiquitination-dependent degradation of Lyn, Hck and Fgr 16. The Cbl-family ubiquitin li...

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Targeting Lyn regulates Snail family shuttling and inhibits metastasis

Cited by 34 publications

References 66 publications

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide-resistant Prostate Cancer

Depletion of Csk preferentially reduces the protein level of LynA in a Cbl-dependent manner in cancer cells

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