β1-Integrin binding to collagen type 1 transmits breast cancer cells into chemoresistance by activating ABC efflux transporters

Baltes, Fabian; Pfeifer, Vladlena; Silbermann, Katja; Caspers, Julia; Rekowski, Kathleen Wantoch von; Schlesinger, Martin; Bendas, Gerd

doi:10.1016/j.bbamcr.2020.118663

Cited by 53 publications

(47 citation statements)

References 48 publications

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“…In a first step, we analyzed the impact of a 24 h cell pretreatment with SCH772984 (1 µM) on the functional activity of ABCG2 ( Figure 6 a) using fluorescent indicator substrates. As previously shown [ 23 ], the presence of COL1 and the downregulation of ITGB1 both increased the efflux activity of ABCG2 in MDA-MB-231 cells. This was confirmed here, considering the data in Figure 6 a.…”

Section: Resultssupporting

confidence: 80%

“…Binding of MDA-MB-231 or MCF-7 BCCs to COL1 activates several signaling pathways and even induces resistance against different antineoplastic drugs. Focusing primarily on ITGB1 in these terms, we established ITGB1 knockdown variants, which displayed a downregulation of ITGB1 to an amount of 21% and 7.5%, respectively [ 23 ]. However, knockdown of ITGB1 did neither reverse the COL1 induced resistance, nor completely circumvented adhesion to COL1 in both cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…In a recent study, we elucidated that COL1 binding of MCF-7 and MDA-MB-231 cells increases the resistance against the breast cancer guideline based cytotoxic agents doxorubicin and mitoxantrone [ 23 ]. Here, we demonstrate the role of DDR1 for ERK1/2 activation upon COL1 binding and the promise of both targets for a single or combined approach.…”

Section: Resultsmentioning

confidence: 99%

“…The chemoresistance of MCF-7 and MDA-MB-231 cells upon cultivation on COL1 has recently been shown by our group to be partly dependent on a subsequent upregulation of ABC drug efflux transporters such as ABCG2 or ABCB1 [ 23 ]. Both transporters can reduce the intracellular levels of cytostatics.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, ITGB1 is described to induce COL1-based CAM-DR in BC and melanoma cells, respectively [ 21 , 22 ]. We have recently reported that COL1 binding of human MCF-7 or MDA-MB-231 BCCs induces the upregulation of ABC efflux transporters, dominantly contributing to the development of a chemoresistance [ 23 ]. However, the underlying molecular mechanisms of the COL1/ABC transporter axis remain to be elucidated especially in light of the findings that ITGB1-knockdown (kd) only partially reverses resistance.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Baltes

Caspers

Henze

et al. 2020

IJMS

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Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Baltes

Caspers

Henze

et al. 2020

IJMS

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The Interaction between Collagen 1 and High Mannose Type CD133 Up‐Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells

Wei,

Geng,

et al. 2023

Advanced Science

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Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer‐associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5‐dependent glutamine uptake and glutathione synthesis. The inhibition of CD133‐COL1 interaction or down‐regulation of SLC1A5 reduces COL1‐accelerated GSCs self‐renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133‐Akt‐SLC1A5 signaling axis, providing a new mechanism underlying the cross‐talk between GSCs and extracellular matrix (ECM) microenvironment.

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Diversity Oriented Synthesis of Novel Xanthones Reveal Potent Doxorubicin‐Inspired Analogs

Meringdal,

Bade,

Bendas

et al. 2024

ChemMedChem

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Inspired by potent antiproliferative xanthone natural products and so far limited examples of derived bioactive agents, a structure activity study of architecturally novel types of xanthones is reported. Their preparation was enabled in a short and divergent manner by a modular chlorination in combination with optimized protocols for a polar condensation and a hetero‐cyclization. Application of these procedures allowed for the synthesis of various polyhalogenated representatives (including mixed bromo/chloro xanthones) that were obtained in up to fourfold improved yields as compared to previous procedures. Subsequent Suzuki coupling of either halide enabled access to phenyl‐ and chloro‐bearing xanthones, which may be functionalized at four out of five non‑hydroxylated positions. Antiproliferative assays against breast cancer cell lines revealed potent activities of some of these simplified analogs that are in the range of pharmaceutically used anticancer drug doxorubicin.

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β1-Integrin binding to collagen type 1 transmits breast cancer cells into chemoresistance by activating ABC efflux transporters

Cited by 53 publications

References 48 publications

Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

The Interaction between Collagen 1 and High Mannose Type CD133 Up‐Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells

Diversity Oriented Synthesis of Novel Xanthones Reveal Potent Doxorubicin‐Inspired Analogs

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