Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cristofaro, Ilaria; Alessandrini, Francesco; Spinello, Zaira; Guerriero, Claudia; Fiore, Mario; Caffarelli, Elisa; Laneve, Pietro; Dini, Luciana; Conti, Luciano; Tata, Ada Maria

doi:10.3390/cells9030657

Cited by 24 publications

(36 citation statements)

References 31 publications

(37 reference statements)

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“…The differential behavior of the SK-N-BE(2C) cell line may be dependent on the expression of the mutated form of p53. In fact, similar results were observed also in the glioblastoma cell line U251 and the GB8 primary glioblastoma cell line, both expressing p53 mutated [ 38 , 42 ]; in both cell lines, the APE treatment caused a progressive accumulation of cells in G2/M phase, suggesting that the tumor cells presenting p53 mutated present a univocal response to APE, regardless of the type of tumor.…”

Section: Discussionsupporting

confidence: 72%

“…The production of ACh by tumor cells and the subsequent interaction with muscarinic receptors frequently activate an autocrine/paracrine loop, modulating cell proliferation, migration and angiogenesis [ 23 ]. Several studies have largely reported the involvement of muscarinic receptors in several primary and metastatic tumors, such as colon [ 24 , 25 ], ovary [ 26 ], prostate [ 27 , 28 , 29 ], lung [ 30 , 31 ] and breast carcinoma [ 32 , 33 , 34 , 35 ], melanoma [ 36 ] and in glioblastoma, as demonstrated by our group [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 63%

“…The role of M2 muscarinic receptors has been largely investigated by our group in recent years, demonstrating its ability to inhibit cell proliferation and survival in primary glioblastoma cell lines [ 37 , 38 , 39 , 40 , 41 , 42 ] as well as in neuroblastoma [ 43 ]. More recently, we have demonstrated that the M2 agonist APE was able to counteract drug resistance in breast cancer, demonstrating the strategic role of the M2 receptor in the therapeutic treatment of different tumor types [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

Luciano

Perciballi

Fiore

et al. 2020

IJMS

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One of the major limits of chemotherapy is depending on the ability of the cancer cells to elude and adapt to different drugs. Recently, we demonstrated how the activation of the M2 muscarinic receptor could impair neuroblastoma cell proliferation. In the present paper, we investigate the possible effects mediated by the preferential M2 receptor agonist arecaidine propargyl ester (APE) on drug resistance in two neuroblastoma cell lines, SK-N-BE and SK-N-BE(2C), a sub-clone presenting drug resistance. In both cell lines, we compare the expression of the M2 receptor and the effects mediated by the M2 agonist APE on cell cycle, demonstrating a decreased percentage of cells in S phase and an accumulation of SK-N-BE cells in G1 phase, while the APE treatment of SK-N-BE(2C) cells induced a block in G2/M phase. The withdrawal of the M2 agonist from the medium shows that only the SK-N-BE(2C) cells are able to rescue cell proliferation. Further, we demonstrate that the co-treatment of low doses of APE with doxorubicin or cisplatin significantly counteracts cell proliferation when compared with the single treatment. Analysis of the expression of ATP-binding cassette (ABC) efflux pumps demonstrates the ability of the M2 agonist to downregulate their expression and that this negative modulation may be dependent on N-MYC decreased expression induced by the M2 agonist. Our data demonstrate that the combined effect of low doses of conventional drugs and the M2 agonist may represent a new promising therapeutic approach in neuroblastoma treatment, in light of its significant impact on drug resistance and the possible reduction in the side effects caused by high doses of chemotherapy drugs.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

Luciano

Perciballi

Fiore

et al. 2020

IJMS

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“…A variant with high homology to this marker is the EGFR which is also over-expressed in cancer [ 36 , 37 ]. Its expression and/or activity can be modulated by muscarinic receptors [ 38 ]. Several authors consider that the sole up-regulation of EGFR expression is a bad prognosis marker and an indicator of chemoresistance in TNBC patients or cell lines [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2 receptor subtype

et al. 2020

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Triple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic receptor agonist respectively, plus paclitaxel reduces cell viability involving a downregulation in the expression of ATP "binding cassette" G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our findings provide substantial evidence about subtype 2 muscarinic receptors as therapeutic targets for the treatment of triple negative tumors.

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“…The upregulation of Notch ligand JAG1 and targets Hey1, Hey2, Hes1 in brain tissues of glioma patients compared to that of healthy brain tissues also highlight the Notch signaling pathway as a potential therapeutic target in glioma patients ( El Hindy et al, 2013 ). The cross interaction among Notch and other pathways, such as Hedgehog ( Chang and Lai, 2019 ) and EGF-related pathways ( Cristofaro et al, 2020 ), implicates the molecular targets with overlapping functions should be prioritized as therapeutic targets. As more in-depth research developed, the contribution of Notch signaling in glioma progression is extended to non-canonical Notch ligand 1 (DLK1).…”

Section: Discussionmentioning

confidence: 99%

TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

et al. 2020

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We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM7, we further determined how the α-kinase-dead mutants of TRPM7 (α-kinase domain deleted/M7-DK and K1648R point mutation/M7-KR) affect Notch activities and CD133 and ALDH1 expression. Lastly, we determined the changes in TRPM7-mediated regulation of glioma cell growth/proliferation, cell cycle, and apoptosis by targeting Notch1. The Oncomine data revealed a significant increase in TRPM7 mRNA expression in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissues. TRPM7 silencing reduced glioma cell growth by inhibiting cell entry into S and G2/M phases and promoting cell apoptosis. TRPM7 expression in GBM cells was found to be positively correlated with Notch1 signaling activity and CD133 and ALDH1 expression; briefly, downregulation of TRPM7 by siTRPM7 decreased Notch1 signaling whereas upregulation of TRPM7 increased Notch1 signaling. Interestingly, kinase-inactive mutants (M7-DK and M7-KR) resulted in reduced activation of Notch1 signaling and decreased expression of CD133 and ALDH1 compared to that of wtTRPM7. Finally, targeting Notch1 effectively suppressed TRPM7-induced growth and proliferation of glioma cells through cell G1/S arrest and apoptotic induction. TRPM7 is responsible for sustained Notch1 signaling activation, enhanced expression of GSC markers CD133 and ALDH1, and regulation of glioma stemness, which contributes to malignant glioma cell growth and invasion.

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Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cited by 24 publications

References 31 publications

The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2 receptor subtype

TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

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