PI3K in stemness regulation: from development to cancer

Madsen, Ralitsa R.

doi:10.1042/bst20190778

Cited by 52 publications

(39 citation statements)

References 143 publications

(190 reference statements)

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“…Many growth factors/receptor tyrosine kinases, Ras, and chemokines/GPCRs signal to activate PI3K, which acts through Akt‐dependent and ‐independent mechanisms [119,120]. Treatment of SCC cells with an EGFR inhibitor decreased p63 protein and mRNA levels [121], whilst exogenous EGF increased ΔNp63 and EGFR/HER2 inhibition prevented this induction [62].…”

Section: Signalling Pathways That Regulate P63 Levels or Activitymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Signalling Pathways That Regulate P63 Levels or Activitymentioning

confidence: 99%

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Pokorná

Vysloužil

Hrabal

et al. 2021

The Journal of Pathology

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“…It has been reported that the activation of the PI3K/AKT cascade is a critical step of survival signaling which mediates apoptosis inhibition via multiple mechanisms [ 45 , 46 ]. The PI3K/AKT signaling is a core pathway for stemness acquisition and maintenance in cancer cells [ 47 ]. Furthermore, in lung cancer, the PI3K/AKT pathway was found to be central to cell survival and proliferation and was detected to be constitutively activated [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway

Daya

Kouba

Ouled-Haddou

et al. 2021

Cancers

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The development of the resistance to platinum salts is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Among the reasons underlying this resistance is the enrichment of cancer stem cells (CSCs) populations. Several studies have reported the involvement of calcium channels in chemoresistance. The Orai3 channel is overexpressed and constitutes a predictive marker of metastasis in NSCLC tumors. Here, we investigated its role in CSCs populations induced by Cisplatin (CDDP) in two NSCLC cell lines. We found that CDDP treatment increased Orai3 expression, but not Orai1 or STIM1 expression, as well as an enhancement of CSCs markers. Moreover, Orai3 silencing or the reduction of extracellular calcium concentration sensitized the cells to CDDP and led to a reduction in the expression of Nanog and SOX-2. Orai3 contributed to SOCE (Store-operated Calcium entry) in both CDDP-treated and CD133+ subpopulation cells that overexpress Nanog and SOX-2. Interestingly, the ectopic overexpression of Orai3, in the two NSCLC cell lines, lead to an increase of SOCE and expression of CSCs markers. Furthermore, CD133+ cells were unable to overexpress neither Nanog nor SOX-2 when incubated with PI3K inhibitor. Finally, Orai3 silencing reduced Akt phosphorylation. Our work reveals a link between Orai3, CSCs and resistance to CDDP in NSCLC cells.

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“…PI3K/Akt plays a critical role in regulating cell proliferation, survival, metabolism, and apoptosis of normal cells (Aoki et al, 2017;Tewari et al, 2019). This signaling pathway is abnormally activated in various tumors, e.g., breast, lung, ovarian, and prostate cancers (Lu et al, 2016;Gu et al, 2018;Ediriweera et al, 2019;Verret et al, 2019;Madsen et al, 2020) and participates in mediating tumor MDR (Guerrero-Zotano et al, 2016;Yang et al, 2017;Li et al, 2019a;Liu et al, 2020). For example, PI3K/Akt signaling pathway is involved in paclitaxel resistance when it is abnormally activated in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

A New Chalcone Derivative C49 Reverses Doxorubicin Resistance in MCF-7/DOX Cells by Inhibiting P-Glycoprotein Expression

Wang

Dong²,

et al. 2021

Front. Pharmacol.

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Objective: C49 is a chalcone derivative. The aim of the current study is to illuminate the efficacy of C49 in reversing multidrug resistance (MDR) in MCF-7/DOX cells and its underlying molecular mechanism.Methods: The cytotoxic effects of C49 on MCF-7/DOX cells were evaluated by MTT assay using different concentration (0–250 μmol/L) of C49. Cell proliferation was evaluated by colony formation assay. Cell death was examined by morphological analysis using Hoechst 33,258 staining. Flow cytometry and immunofluorescence were utilized to evaluate the intracellular accumulation of doxorubicin (DOX) and cell apoptosis. The differentially expressed genns between MCF-7 and MCF-7/DOX cells were analyzed by GEO database. The expression of PI3K/Akt pathway proteins were assessed by Western blot The activities of C49 combined with DOX was evaluated via xenograft tumor model in female BALB/c nude mice.Results: C49 inhibited the growth of MCF-7 cells (IC50 = 59.82 ± 2.10 μmol/L) and MCF-7/DOX cells (IC50 = 65.69 ± 8.11 μmol/L) with dosage-dependent and enhanced the cellular accumulation of DOX in MCF-7/DOX cells. The combination of C49 and DOX inhibited cell proliferation and promoted cell apoptosis. MCF-7/DOX cells regained drug sensibility with the combination treatment through inhibiting the expression of P-gp, p-PI3K and p-Akt proteins. Meanwhile, C49 significantly increased the anticancer efficacy of DOX in vivo.Conclusion: C49 combined with DOX restored DOX sensitivity in MCF-7/DOX cells through inhibiting P-gp protein.

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PI3K in stemness regulation: from development to cancer

Cited by 52 publications

References 143 publications

The foggy world(s) of p63 isoform regulation in normal cells and cancer

The foggy world(s) of p63 isoform regulation in normal cells and cancer

Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway

A New Chalcone Derivative C49 Reverses Doxorubicin Resistance in MCF-7/DOX Cells by Inhibiting P-Glycoprotein Expression

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