Inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy

Liu, Sanying; Zha, Ji; Lei, Ming

doi:10.1007/s12094-017-1724-0

Cited by 38 publications

(37 citation statements)

References 31 publications

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“…The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway and the Hippo pathway were reportedly associated with cell proliferation, differentiation, migration, senescence, and apoptosis [17][18] . Previous studies have shown that alteration of the MEK/ERK pathway is strongly implicated in ovarian cancer pathogenesis [19][20] . Dang et al, [21] reported that metformin combined with cisplatin inhibited cell viability and promoted apoptosis of human ovarian cancer cells by inactivating ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

Shi

Chen

Han

et al. 2020

Preprint

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Background Wnt inducible signaling protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on proliferation and migration of ovarian cancer cells in vitro and in vivo . Results Immunohistochemistry and western blot results indicated that WISP2 was highly expressed in various ovarian tissues and cell lines. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells. WISP2 deletion promoted cell apoptosis and affected the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of extracellular signal-related kinase (p-ERK)1/2, as well as CEBPα and CEBPβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP). Conclusion WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.

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Section: Discussionmentioning

confidence: 99%

WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

Shi

Chen

Han

et al. 2020

Preprint

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“…Activation of the MAPK signaling pathway is one of the most frequent events in cancer and affects many features inherent to malignant cells [32,46]. Most notably, high activity of the MEK1/2-ERK1/2 portion of the MAPK cascade directly promotes cell proliferation, survival, and drug resistance [31][32][33]47]. Furthermore, a number of studies reported that ERK1/2 activation occurs in CSCs [27] and is crucial for cell survival and proliferation in prostate, breast, and thyroid tumors [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, cisplatin treatment of HGSOC cells results in further MEK1/2 pathway activation that persists in cisplatin-resistant cells. MEK1/2-ERK1/2 signaling inhibition in ovarian cancer cells is reported to sensitize them to chemotherapy [47], so MEK1/2 pathway hyperactivation could be a mechanism allowing HGSOC cells to overcome cytotoxic effects of cisplatin. Cisplatin-induced MEK1/2 activation in OVCAR8 and PEO4 cell lines established from recurrent tumors, which already obtained cisplatin resistance [52][53][54], suggests that repeated cisplatin treatment can further promote MEK1/2-ERK1/2 activity and associated chemoresistance in HGSOC.…”

Section: Discussionmentioning

confidence: 99%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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“…In addition, MNK1 knockdown and inhibition decreased ovarian cancer cell viability [57]. Liu et al demonstrated that MNK1 is involved in the resistance of ovarian cancer cells to chemotherapy [156]. They observed increased phosphorylation levels of ERK, MNK1, and eIF4E in ovarian cancer cells exposed to chemotherapy, as well as in ovarian cancer patients.…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

Pinto-Díez

Ferreras-Martín

Carrión-Marchante

et al. 2020

IJMS

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The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

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Inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy

Abstract: Our work shows that ERK/Mnk/eIF4E activation is critically involved in ovarian cancer chemoresistance and inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy.

Cited by 38 publications

References 31 publications

WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

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