PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

Fang, Hehui; Jin, Juan; Huang, Doudou; Yang, Fang; Guan, Xiaoxiang

doi:10.1111/cas.13593

Cited by 27 publications

(26 citation statements)

References 33 publications

(73 reference statements)

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“…PAI-1 is one of the most important adipokines. Simultaneously, PAI-1 exerts various effects on multiple aspects of cancer progression, including migration, invasion and apoptosis [20][21][22][23]. Thus, we evaluated whether PAI-1 was secreted by adipocytes or paracrinically secreted by breast cancer cells using ELISA assays.…”

Section: Activation Of Plod2 In Caas Is Responsible For the Collagen mentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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Background: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear. Methods: Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co-implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes. Results: It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer. Conclusion: In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

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Section: Activation Of Plod2 In Caas Is Responsible For the Collagen mentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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“…PAI-1 regulates tumour growth through angiogenesis and is involved in the migration, invasion and adhesion of cancer cells [17][18][19] . PAI-1 is also associated with multi-drug resistance 13,20 . A high expression of PAI-1 leads to drug resistance, which indicates that targeting PAI-1 is an important strategy for the treatment of GBM.…”

Section: Introductionmentioning

confidence: 99%

ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma

et al. 2019

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PAI-1 plays significant roles in cancer occurrence, relapse and multidrug resistance and is highly expressed in tumours. ACT001, which is currently in phase I clinical trials for the treatment of glioblastoma (GBM). However, the detailed molecular mechanism of ACT001 is still unclear. In this study, we investigated the effects of ACT001 on glioma cell proliferation and clarified its mechanism. We discovered that PAI-1 was the direct target of ACT001 by a cellular thermal shift assay. Then, the interaction between ACT001 and PAI-1 was verified by Biacore assays, thermal stability assays and ACT001 probe assays. Furthermore, from the proteomic analysis, we found that ACT001 directly binds PAI-1 to inhibit the PI3K/AKT pathway, which induces the inhibition of glioma cell proliferation, invasion and migration. Moreover, the combination of ACT001 and cisplatin showed a synergistic effect on the inhibition of glioma in vitro and in vivo. In conclusion, our findings demonstrate that PAI-1 is a new target of ACT001, the inhibition of PAI-1 induces glioma inhibition, and ACT001 has a synergistic effect with cisplatin through the inhibition of the PAI-1/PI3K/AKT pathway.

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“…In AML, KIT inhibition by imatinib and nilotinib was shown to be overcome in the presence of the cytokine G‐CSF (Gordon et al , ). The cytokine C‐C motif chemokine 5 (CCL5, previously known as RANTES) is physiologically a regulator of immune cell migration and was identified as constituting a distinct chemokine release cluster in AML (Bruserud et al , ) and as an important drug resistance mediator in several tumor entities: In breast, ovarian, and prostate cancer, CCL5 rendered tumor cells resistant to tamoxifen, saracatinib, cisplatin, or taxanes, respectively (Fang et al , ; Kato et al , ; Pasquier et al , ; Xiang et al , ; Yi et al , ; Zhou et al , ). In addition, CCL5 was found to contribute to tumor progression and metastasis (Azenshtein et al , ; Velasco‐Velázquez et al , ).…”

Section: Introductionmentioning

confidence: 99%

CCL5 mediates target‐kinase independent resistance to FLT3 inhibitors in FLT3‐ITD‐positive AML

et al. 2020

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FLT3‐ITD tyrosine kinase inhibitors (TKI) show limited clinical activity in acute myeloid leukemia (AML) due to emerging resistance. TKI resistance is mediated by secondary FLT3‐ITD mutations only in a minority of cases. We hypothesize that the cytokine CCL5 protects AML cells from TKI‐mediated cell death and contributes to treatment resistance. We generated PKC412‐ and sorafenib‐resistant MOLM‐13 cell lines as an in vitro model to study TKI resistance in AML. Increased CCL5 levels were detected in supernatants from PKC412‐resistant cell lines compared to TKI‐sensitive cells. Moreover, CCL5 treatment of TKI‐sensitive cells induced resistance to PKC412. In resistant cell lines with high CCL5 release, we observed a significant downregulation of the CCL5‐receptor CCR5 and CXCR4. In these cell lines, TKI resistance could be partly overcome by addition of the CXCR4‐receptor antagonist plerixafor. Microarray and intracellular flow cytometry analyses revealed increased p‐Akt or p‐Stat5 levels in PKC412‐resistant cell lines releasing high amounts of CCL5. Treatment with the CXCR4 antagonist plerixafor, αCCL5, or CCR5‐targeting siRNA led to a decrease of p‐Akt‐positive cells. Transient transfection of sensitive MOLM‐13 cells with a CCL5‐encoding vector mediated resistance against PKC412 and led to an increase in p‐Akt‐positive and p‐Stat5‐positive cells. Isolated AML blasts from patients treated with PKC412 revealed that CCL5 transcript levels increase significantly at relapse. Taken together, our findings indicate that CCL5 mediates resistance to FLT3‐TKIs in FLT3‐ITD‐mutated AML and could possibly serve as a biomarker to predict drug resistance.

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PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

Cited by 27 publications

References 33 publications

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma

CCL5 mediates target‐kinase independent resistance to FLT3 inhibitors in FLT3‐ITD‐positive AML

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