Cell-cell and cell-substratum contacts in the regulation of MAPK and Akt signalling: Importance in therapy, biopharmacy and bioproduction

Stulpinas, Aurimas; Uzusienis, Tomas; Imbrasaitė, Aušra; Krestnikova, Natalija; Unguryte, Ausra; Kalvelytė, Audronė

doi:10.1016/j.cellsig.2021.110034

Cited by 4 publications

(11 citation statements)

References 87 publications

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“…The continuous cell line A549 was taken as a basis for comparison. Our previous studies using flow cytometry analysis showed that established human non-small cell lung cancer primary cell lines variously expressed putative lung cancer stem cell surface markers ( 34 ). In Figure 1 , we present a further characterization of these cells in culture.…”

Section: Resultsmentioning

confidence: 99%

“…These data are consistent with our previously demonstrated role of FAK inhibition on ERK kinase in A549 cells: FAK inhibitor promoted ERK phosphorylation in A549 cells. Likewise, abnormal activation of ERK1/2 in lung cancer A549 cells, in contrast to downregulation in other cell lines studied, was determined in an anchorage-independent state ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

“…Given that non-genetic modulation of cell state can strongly affect cell signaling, including interactions between signaling pathways, and that cell state dictates drug sensitivity, we studied the interaction between AKT and ERK signaling molecules in cells that lose contact with the substrate. It may be that circulating tumor cells, key players in metastatic dissemination, may respond differently to anticancer drugs than cells adherent to the extracellular substrate ( 34 ). Activation of MAP and AKT kinase cascades is known to involve regulatory events initiated by extracellular contacts through activation of integrins and downstream focal adhesion kinase FAK.…”

Section: Discussionmentioning

confidence: 99%

“…Downstream of the integrin and growth factor receptors, FAK activates multiple targets, including AKT. We have previously shown that FAK is involved in the transmission of integrin-induced signaling to ERK and AKT in muscle stem cells and lung cancer cells ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…Human primary lung cancer cell lines were established from surgical material (Regional bioethical approval no. 158200-18/5-1024-537) as previously described ( 34 ). Briefly, lung tumor specimens from 9 patients were minced, washed, and enzymatically digested.…”

Section: Methodsmentioning

confidence: 99%

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Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

et al. 2023

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There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

et al. 2023

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Understanding and targeting anoikis in metastasis for cancer therapies

Fard

Jalilzadeh

Mehdizadeh

et al. 2022

Cell Biology International

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The development of effective treatments for cancers requires investigations for a more detailed and comprehensive understanding of the basic cellular mechanisms involved in carcinogenesis, cancer progression, and metastasis. One of those driving mechanisms is anoikis, a special type of apoptosis, which is induced by losing anchorage from the extracellular matrix (ECM). In other words, resisting death in detached cells (cells without ECM) forms an anoikis‐resistant phenotype. Since the anoikis‐resistance state compensates for the initial steps of cancer metastasis, this review aimed to discuss mechanisms of gaining anoikis/anoikis resistance phenotype in tumor cells. Finally, we highlighted the significance of anoikis in malignancies so as to provide clear insight into cancer diagnosis and therapy development.

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The Role and Efficacy of JNK Inhibition in Inducing Lung Cancer Cell Death Depend on the Concentration of Cisplatin

Stulpinas,

Tenkutytė,

Imbrasaitė

et al. 2024

ACS Omega

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Cell-cell and cell-substratum contacts in the regulation of MAPK and Akt signalling: Importance in therapy, biopharmacy and bioproduction

Cited by 4 publications

References 87 publications

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

Understanding and targeting anoikis in metastasis for cancer therapies

The Role and Efficacy of JNK Inhibition in Inducing Lung Cancer Cell Death Depend on the Concentration of Cisplatin

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