Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Abstract. Cancer stem cells (CSCs) have central functions in cancer formation and development. Aberrant expression of AKT, ERK and NF-κB signaling pathways have been reported in several types of CSCs. Phytochemicals from dietary compounds possess anti-CSC properties, and have been characterized as promising therapeutic agents for the prevention and treatment of many types of cancers. We previously showed that the newly synthesized genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylygenistein (DFOG), can inhibit the self-renewal ability of ovarian cancer stem cells (OVCSLCs). In the present study, we further assessed whether various signaling pathways are regulated by DFOG. We found that spheroids derived from the SKOV3 cell line possessed OVCSLC properties and DFOG efficiently inhibited the stemness of the OVCSLCs. In addition, the suppression of spheroid and colony formation by DFOG was associated with inhibition of AKT and ERK1/2 protein phosphorylation, and NF-κB activity in OVCSLCs from the SKOV3 cells. Importantly, DFOG inhibited the oncogenicity of the OVCSLCs by activation of FoxO3a and/or inactivation of FoxM1 by the targeting of multiple pro-survival (AKT and ERK1/2) and proinflammatory (NF-κB) pathways, providing a new avenue for the treatment of ovarian carcinoma in humans.

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“…Numerous signaling pathways regulate cell growth and proliferation (28). Various molecules are associated with tumor development.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Ning

Cao

et al. 2017

Oncology Reports

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“…Here we show that fragment N2 potently inhibits FGF1-induced phosphorylation of ERK2 and Akt. Because both Akt and ERK2 participate in cell survival signaling (69), one possibility to explain the capacity of fragment N2 to sensitize tumor cells to anti-cancer treatment is a shutdown of pro-survival pathways. There is, however, no evidence for such mechanisms in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Cailliau

Lescuyer

Burnol

et al. 2015

Journal of Biological Chemistry

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Background: RasGAP and its stress-activated caspase-3-generated fragments N and N2 have the potential to regulate receptor tyrosine kinase (RTK) signaling. Results: RasGAP and fragment N favor FGF1-mediated signaling via different mechanisms, whereas fragment N2 blocks it. Conclusion: Stress, via the cleavage of RasGAP, modulates RTK signaling. Significance: This work provides a mechanistic framework of how stress impacts on cell signaling.

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“…Apart from implications in neurodevelopmental disorders, both pathways are extensively described in tumorigenesis 17 and many of the above mentioned syndromes are associated with a higher risk for the development of benign and/or malignant tumors.…”

Section: Ptpn11 Variant and Mcap Syndrome D Döcker Et Almentioning

confidence: 99%

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

et al. 2014

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Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactylythus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A4G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (4100 Â coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (41000 Â coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G4A; p. (Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

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Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Cited by 521 publications

References 214 publications

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

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