Microtubule inhibition causes epidermal growth factor receptor inactivation in oesophageal cancer cells

Wu, Xuping; Sooman, Linda; Lennartsson, Johan; Bergström, Stefan; Bergqvist, Michael; Gullbo, Joachim; Ekman, Simon

doi:10.3892/ijo.2012.1710

Cited by 17 publications

(18 citation statements)

References 33 publications

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“…We have previously shown that the disruption of the microtubule system by PPT or vincristine causes the dephosphorylation and degradation of the EGFR (26). We obtained similar results in this work using PPP (Fig.…”

Section: Discussionsupporting

confidence: 80%

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Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

Sooman

Wickström

et al. 2013

Molecular Cancer Therapeutics

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The insulin-like growth factor-1 (IGF-I) and its receptors play an important role in transformation and progression of several malignancies. Inhibitors of this pathway have been developed and evaluated but generally performed poorly in clinical trials, and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective IGF-IR inhibitor and is currently undergoing clinical trials. We investigated PPP's activity in panels of human cancer cell lines (e.g., esophageal squamous carcinoma cell lines) but found no effects on the phosphorylation or expression of IGF-IR. Nor was the cytotoxic activity of PPP related to the presence or spontaneous phosphorylation of IGF-IR. However, its activity correlated with that of known tubulin inhibitors, and it destabilized microtubule assembly at cytotoxic concentrations also achievable in patients. PPP is a stereoisomer of podophyllotoxin (PPT), a potent tubulin inhibitor, and an equilibrium between the two has previously been described. PPP could thus potentially act as a reservoir for the continuous generation of low doses of PPT. Interestingly, PPP also inhibited downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. This effect is associated with microtubule-related downregulation of the EGF receptor, rather than the IGF-IR. These results suggest that the cytotoxicity and pAkt inhibition observed following treatment with the cyclolignan PPP in vitro result from microtubule inhibition (directly or indirectly by spontaneous PPT formation), rather than any effect on IGF-IR. It is also suggested that PPT should be used as a reference compound in all future studies on PPP. Mol Cancer Ther; 12(8); 1526-36. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 80%

“…EGFR but not IGF-IR (26). Therefore, we investigated whether PPP had similar effects on EGFR, which was expressed in all of the ESCC cell lines in the panel (not shown).…”

Section: Ppp Inhibits Egfr and Decreases Downstream Signaling From Tymentioning

confidence: 99%

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

Sooman

Wickström

et al. 2013

Molecular Cancer Therapeutics

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“…Addition of Docetaxel, PPT and Vincristine inhibited the phosphorylated form of Akt, while PPT and Vincristine resulted in decreased phosphorylation of Erk. The effects of microtubule disruption on EGFR activity were diminished when a phosphatase inhibitor was added . These results effectively link the microtubule network to EGFR activity .…”

Section: Discussionmentioning

confidence: 74%

“…We also report accelerated entry into catagen and completion of the first hair cycle in mice with genetic deletion of Stmn1, suggesting that the deregulation of microtubule dynamics in follicular keratinocytes is involved in catagen. Wu and colleagues using microtubule‐destabilizing agents in oesophageal carcinoma lines established the relationship between EGFR and the microtubule network . They report a decrease in EGFR phosphorylation following treatment with taxol and PPT.…”

Section: Discussionmentioning

confidence: 99%

The epidermal growth factor receptor decreases Stathmin 1 and triggers catagen entry in the mouse

Bichsel

Hammiller

Trempus

et al. 2016

Experimental Dermatology

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The epidermal growth factor receptor (EGFR) is necessary for normal involution of hair follicles after the growth phase of anagen, although the mechanisms through which it acts are not well understood. In this report, we used transcriptional profiling of microdissected hair follicles from mice with skin-targeted deletion of Egfr to investigate how EGFR activation triggers catagen. Immunofluorescence for phospho-EGFR in mouse skin revealed increased activation of EGFR in follicular keratinocytes at catagen onset. Consistent with other models of EGFR deficiency, mice with skin-targeted deletion of Egfr (Krt14-Cre(+) /Egfr(fl/fl) ) exhibited a delayed and asynchronous catagen entry. Transcriptional profiling at the time of normal catagen onset at post-natal day (P) 17 revealed increased expression of the mitotic regulator Rcc2 in hair follicles lacking EGFR. Rcc2 protein was strongly immunopositive in the nuclei of control follicular keratinocytes at P16 then rapidly decreased until it was undetectable between P18 and 21. In contrast, Rcc2 expression continued in Egfr mutant follicles throughout this period. Proliferation, measured by bromodeoxyuridine incorporation, was also significantly increased in Egfr mutant follicular keratinocytes compared to controls at P18-21. Similarly, Rcc2-regulated mitotic regulator Stathmin 1 was strikingly reduced in control but not Egfr mutant follicles between P17 and P19. Deletion of Stmn1, in turn, accelerated catagen entry associated with premature cessation of proliferation in the hair follicles. These data reveal EGFR suppression of mitotic regulators including Rcc2 and Stathmin 1 as a mechanism for catagen induction in mouse skin.

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“…Our results indicate that Tau is a key inhibitor of wild-type EGFR signaling in gliomas. Accordingly, drugs that interfere with microtubule function have been associated with EGFR inactivation in other cancers (43), as they seem to alter endocytic trafficking (11). Moreover, it has been shown that microtubule acetylation, which is promoted by Tau function (16), promotes the degradation of EGFR through changes in the microtubule-dependent endocytic trafficking (17).…”

Section: Tau Expression Is a Surrogate Marker Of The Less Aggressive mentioning

confidence: 99%

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Gargini

Segura-Collar

Herránz

et al. 2019

Preprint

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One Sentence SummaryTau, which is induced by IDH mutations, inhibits the EGFR/NF-kB/TAZ axis and impairs the mesenchymal/pericyte-like transformation of glioma cells, normalizing the vasculature and impairing tumor aggressiveness. AbstractMutant IDH1/2 gliomas represent a more indolent form of cancer. However, how this group of tumors evolve, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau, a gene classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wild-type and mutant IDH1/2 in gliomas. Moreover, the level of Tau decreases when the tumor progresses. Besides, Tau is almost absent from tumors with EGFR mutations, whereas its expression is inversely correlated with overall survival in gliomas carrying wild-type or amplified EGFR. Here, we demonstrate that the overexpression of Tau, through the stabilization of microtubules, impairs the mesenchymal/pericyte-like transformation of glioma cells by blocking the EGFR-NFB-TAZ axis. However, mutant EGFR induces a constitutive activation of this pathway, which is no longer sensitive to Tau. By inhibiting the phenotypic plasticity of EGFRamp/wt glioma cells, Tau protein inhibits angiogenesis and favors vascular normalization, decreasing tumor aggressiveness and rendering the tumors more sensitive to chemotherapy.

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Microtubule inhibition causes epidermal growth factor receptor inactivation in oesophageal cancer cells

Cited by 17 publications

References 33 publications

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

The epidermal growth factor receptor decreases Stathmin 1 and triggers catagen entry in the mouse

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

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