Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Alcalá, Sonia; Mayoral-Varo, Víctor; Ruiz-Cañas, Laura; López-Gil, Juan Carlos; Heeschen, Christopher; Martı́n-Pérez, Jorge; Sáinz, Bruno

doi:10.3390/ijms21207437

Cited by 21 publications

(14 citation statements)

References 95 publications

(149 reference statements)

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“…Increased activity of Src was reported to promote hyper-proliferation, migration, invasion and epithelial-to-mesenchymal transition during cancer progression (Guarino 2010 ). Src was over-expressed and activated in PDAC (Alcalá et al 2020 ), which promoted the metastasis of PDAC (Ogawa et al 2019 ). LY-1816, a Src inhibitor, has been demonstrated to have clinical therapeutic effect on PDAC (Yang et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Desmoglein 3 contributes to tumorigenicity of pancreatic ductal adenocarcinoma through activating Src–FAK signaling

Yimamumaimaitijiang

Tuniyazi

et al. 2021

Animal Cells and Systems

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Desmogleins (DSGs), with the ability to link adjacent cells, have been shown to participate in the development of malignancy. DSG3 was up-regulated in various cancers, including lung, head and neck, and esophagus squamous cell carcinoma, which contributed to the tumor progression. The role of DSG3 in pancreatic ductal adenocarcinoma (PDAC) still remains elusive. Here, the expression of DSG3 was found to be enhanced in pancreatic cancer cell lines in vitro. Functional assays showed that shRNA-mediated knockdown of DSG3 decreased cell viability of pancreatic cancer cells and retarded the cell proliferation, migration and invasion. However, pcDNAmediated over-expression of DSG3 exhibited reversed effect on pancreatic cancer cell progression. In addition, the in vivo assay demonstrated that transfection of shDSG3 lentiviruses into pancreatic cancer cells repressed the tumorigenicity of PDAC after the cancer cells were transplanted into mice subcutaneously. Elevated DSG3 expression promoted the phosphorylation of Src (p-Src), focal adhesion kinase (p-FAK) and AKT (p-AKT) in vitro, while silence of DSG3 reduced the expression of p-Src, p-FAK and p-AKT both in vitro and in vivo. In conclusion, DSG3, as an oncogene, contributed to the tumorigenicity of PDAC through activating Src-FAK signaling.

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Section: Discussionmentioning

confidence: 99%

Desmoglein 3 contributes to tumorigenicity of pancreatic ductal adenocarcinoma through activating Src–FAK signaling

Yimamumaimaitijiang

Tuniyazi

et al. 2021

Animal Cells and Systems

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“…PI3KR1 expression is associated with lymphangiogenesis, lymphatic metastasis, and survival in PC [ 101 , 102 ]. Src (encoded by SRC ) is an oncogenic kinase that regulates EMT, migration, invasion, cell adhesion and spreading, metastasis, stem-like features, proliferation, growth, angiogenesis, and survival of PC cells, and its expression and activity are further correlated with the survival, progression, and therapy response rate of patients with PC [ 103 – 114 ]. Signal transducer and activator of transcription (STAT)-3 (encoded by STAT3 ) induces initiation, progression, proliferation, metastasis, angiogenesis, EMT, self-renewal stemness, migration, invasion, immune escape, and resistance to anoikis, chemotherapy, and radiotherapy of PC cells, and its activation is associated with poor prognosis of patients with PC [ 115 – 121 ].…”

Section: Discussionmentioning

confidence: 99%

Exploration of the System-Level Mechanisms of the Herbal Drug FDY003 for Pancreatic Cancer Treatment: A Network Pharmacological Investigation

Lee

Lee²,

Kang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Pancreatic cancer (PC) is the most lethal cancer with the lowest survival rate globally. Although the prescription of herbal drugs against PC is gaining increasing attention, their polypharmacological therapeutic mechanisms are yet to be fully understood. Based on network pharmacology, we explored the anti-PC properties and system-level mechanisms of the herbal drug FDY003. FDY003 decreased the viability of human PC cells and strengthened their chemosensitivity. Network pharmacological analysis of FDY003 indicated the presence of 16 active phytochemical components and 123 PC-related pharmacological targets. Functional enrichment analysis revealed that the PC-related targets of FDY003 participate in the regulation of cell growth and proliferation, cell cycle process, cell survival, and cell death. In addition, FDY003 was shown to target diverse key pathways associated with PC pathophysiology, namely, the PIK3-Akt, MAPK, FoxO, focal adhesion, TNF, p53, HIF-1, and Ras pathways. Our network pharmacological findings advance the mechanistic understanding of the anti-PC properties of FDY003 from a system perspective.

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“…Our results showed that the inactivating mutation of the SH2 and SH3 domains R175 L and W118 A /R175 L significantly reduced BCSCs renewal in both cell lines, supporting the relevance of the adapter domains in the renewal of the tumor initiating cells. In primary PDAC cultures, established from patient-derived xenografts with Dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

Mayoral-Varo

Sánchez-Bailón

Calcabrini

et al. 2021

Cancers

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The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.

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Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Cited by 21 publications

References 95 publications

Desmoglein 3 contributes to tumorigenicity of pancreatic ductal adenocarcinoma through activating Src–FAK signaling

Desmoglein 3 contributes to tumorigenicity of pancreatic ductal adenocarcinoma through activating Src–FAK signaling

Exploration of the System-Level Mechanisms of the Herbal Drug FDY003 for Pancreatic Cancer Treatment: A Network Pharmacological Investigation

The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

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