Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

Pappalardo, Francesco; Russo, Giulia; Candido, Saverio; Pennisi, Marzio; Cavalieri, Salvatore; Motta, Santo; McCubrey, James A.; Nicoletti, Ferdinando; Libra, Massimo

doi:10.1371/journal.pone.0152104

Cited by 53 publications

(41 citation statements)

References 20 publications

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“…This experiment confirmed that AKT phosphorylation promoted the phosphorylation of ERK1/2 and NF-κB and that the PI3K/AKT pathway positively regulated ERK1/2 and NF-κB signaling pathways. Our results also confirmed that ERK1/2 signaling negatively regulated the PI3K/AKT signaling pathway and positively regulated NF-κB signaling, consistent with previously reported experimental results [34,[48][49][50][51][52]. In this study, the pharmacodynamic analyses were consistent with the results of q-PCR and Western blot, which showed that Kaji-ichigoside F1 and Rosamultin could inhibit mitochondrial apoptosis by altering the expression of mitochondrial apoptosis-related genes, including Bcl-2, Bax, Cyt C, caspase 9, and caspase 3.…”

supporting

confidence: 92%

Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway

Shi

Zhan

et al. 2020

Oxidative Medicine and Cellular Longevity

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As a pair of differential isomers, Kaji-ichigoside F1 and Rosamultin are both pentacyclic triterpenoids isolated from the subterranean root of Potentilla anserina L., a plant used in folk medicine in western China as antihypoxia and anti-inflammatory treatments. We demonstrated that Kaji-ichigoside F1 and Rosamultin effectively prevented hypoxia-induced apoptosis in vascular endothelial cells. We established a hypoxia model, using EA.hy926 cells, to further explore the mechanisms. Hypoxia promoted the phosphorylation of AKT, ERK1/2, and NF-κB. In hypoxic cells treated with Kaji-ichigoside F1, p-ERK1/2 and p-NF-κB levels were increased, while the level of p-AKT was decreased. Treatment with Rosamultin promoted phosphorylation of ERK1/2, NF-κB, and AKT in hypoxic cells. Following the addition of LY294002, the levels of p-AKT, p-ERK1/2, and p-NF-κB decreased significantly. Addition of PD98059 resulted in reduced levels of p-ERK1/2 and p-NF-κB, while p-AKT levels were increased. Pharmacodynamic analysis demonstrated that both LY294002 and PD98059 significantly inhibited the positive effects of Kaji-ichigoside F1 on cell viability during hypoxia, consistent with the results of hematoxylin-eosin (H&E) staining, DAPI staining, and flow cytometry. The antihypoxia effects of Rosamultin were remarkably inhibited by LY294002 but promoted by PD98059. In Kaji-ichigoside F1- and Rosamultin-treated cells, Bcl2 expression was significantly upregulated, while expression of Bax and cytochrome C and levels of cleaved caspase-9 and cleaved caspase-3 were reduced. Corresponding to pharmacodynamic analysis, LY294002 inhibited the regulatory effects of Kaji-ichigoside F1 and Rosamultin on the above molecules, while PD98059 inhibited the regulatory effects of Kaji-ichigoside F1 but enhanced the regulatory effects of Rosamultin. In conclusion, Kaji-ichigoside F1 protected vascular endothelial cells against hypoxia-induced apoptosis by activating the ERK1/2 signaling pathway, which positively regulated the NF-κB signaling pathway and negatively regulated the PI3K/AKT signaling pathway. Rosamultin protected vascular endothelial cells against hypoxia-induced apoptosis by activating the PI3K/AKT signaling pathway and positively regulating ERK1/2 and NF-κB signaling pathways.

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supporting

confidence: 92%

Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway

Shi

Zhan

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Another strategy of cancer cells used to inhibit the efficacy of treatment is enhanced expression of pathways involved in cancer proliferation and survival. With regard to melanoma RAS-RAF-MEK-ERK (MAPK, mitogenactivated protein kinase) and PI3K-AKT signalling pathways can be differentiated, which in addition can interact with each other [64,65]. They are activated, among others, by NRAS, BRAF mutations as well as by loss of PTEN properties (PI3K kinase phosphatase) and stimulation of growth factors including VEGF.…”

Section: Survival and Proliferation Pathwaysmentioning

confidence: 99%

Resistance of melanoma cells to anticancer treatment: a role of vascular endothelial growth factor

Bogusławska-Duch

Ducher

Małecki

2020

pdia

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A b s t r a c tMelanoma is one of the most aggressive and resistant to treatment neoplasms. There are still many challenges despite many promising advances in anticancer treatment. Currently, the main problem for all types of treatment is associated with heterogeneity. Due to heterogeneity of cancer cells, "precise" targeting of a medicine against a single phenotype limits the efficacy of treatment and affects resistance to applied therapy. Therefore it is important to understand aetiology and reasons for heterogeneity in order to develop effective and long-lasting treatment. This review summarises roles of vascular endothelial growth factor (VEGF) that may stimulate growth of a melanoma tumour irrespective of its proangiogenic effects, contributing to cancer heterogeneity. VEGF triggers processes associated with extracellular matrix remodelling, cell migration, invasion, angiogenesis, inhibition of immune responses and favours phenotypic plasticity and epithelial-mesenchymal transition. Consequently, it participates in mechanisms of interactions between melanoma cancer cells and microenvironment and it can modify sensitivity to therapeutic factors.

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“…63,64 The widely observed mechanisms are mutation of neuroblastoma-RAS (NRAS mutations-NRAS Q61 ; NRAS T58 ; NRAS G13R ), 65 loss of neurofibromatosis type-1(NF1), 66-68 loss of phosphatase and tensin homolog (PTEN), 69,70 up-regulation of cancer Osaka thyroid kinase (COT), 71 mutation of MEK, 63,69 negative feedback inactivation of extracellular-related kinase (ERK) and alteration in phosphoinositide 3-kinase-AKT (PI3K-AKT) pathway. 64,72 …”

Section: P53mentioning

confidence: 99%

Chemotherapy resistance mechanisms in advanced skin cancer

2017

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Melanoma is a most dangerous and deadly type of skin cancer, and considered intrinsically resistant to both radiotherapy and chemotherapy. It has become a major public health concern as the incidence of melanoma has been rising steadily over recent decades with a 5-year survival remaining less than 5%. Detection of the disease in early stage may be curable, but late stage metastatic disease that has spread to other organs has an extremely poor prognosis with a median survival of less than 10 months. Since metastatic melanoma is unresponsive to therapy that is currently available, research is now focused on different treatment strategies such as combinations of surgery, chemotherapy and radiotherapy. The molecular basis of resistance to chemotherapy seen in melanoma is multifactorial; defective drug transport system, altered apoptotic pathway, deregulation of apoptosis and/or changes in enzymatic systems that mediate cellular metabolic machinery. Understanding of alterations in molecular processes involved in drug resistance may help in developing new therapeutic approaches to treatment of malignant melanoma.

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Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

Cited by 53 publications

References 20 publications

Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway

Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway

Resistance of melanoma cells to anticancer treatment: a role of vascular endothelial growth factor

Chemotherapy resistance mechanisms in advanced skin cancer

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