EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D<sub>3</sub>in acute myeloid leukemia cells

Lainey, Élodie; Wolfromm, Alice; Sukkurwala, Abdul Qader; Micol, Jean-Baptiste; Fenaux, Pierre; Galluzzi, Lorenzo; Kepp, Oliver

doi:10.4161/cc.26016

Cited by 39 publications

(17 citation statements)

References 62 publications

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“…Like uPA (ATF) in the present study, Erlotinib is known to affect EGF effects by downregulating ERK1/2 and AKT [31,32]. But in contrast to the current study, where uPA (ATF) induced p38 and Src, Erlotinib was shown to potently inhibit phosphorylation of p38 and Src family kinases [33]. Together, these findings suggest that the negative effect of uPA (ATF) on EGF signalling is mediated downstream from an activated EGFR.…”

Section: Discussioncontrasting

confidence: 89%

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Kozlova

Samoylenko

Drobot

et al. 2015

Molecular Carcinogenesis

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The epidermal growth factor receptor (EGFR) is involved in the regulation of various cellular processes and dysregulation of its signalling plays a critical role in the etiology of a variety of malignancies like breast cancer. At the same time, elevated levels of urokinase (uPA), its receptor uPAR, and other components of the plasminogen activation system are found to be correlated with a poor prognosis in breast cancer. Interestingly, EGFR appears to participate in transducing the signal generated upon binding of uPA to uPAR. However, whether uPA signalling would thereby interfere with ligand-driven EGFR signalling was not described before. Therefore, it was the aim of the present study to investigate the combined effects of uPA and EGF in the low invasive and high invasive breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, respectively. Simultaneous exposure of cells to both signals negatively affected ERK1/2 and AKT activation whereas positive effects on p38 and Src kinase phosphorylation were noted in both cell lines. Furthermore, uPA attenuated the mitogenic effect of EGF on cellular proliferation, invasion and motility in both MCF-7 and MDA-MB-231 cells. Experiments with the uPA amino terminal fragment (ATF) revealed that the negative effects of uPA were independent from its protease activity. Together, these data suggest that enhanced levels of uPA in breast cancer modulate the mitogenic effects of EGF and thus, this knowledge may help to better understand breast cancer pathogenesis as well as to develop new therapeutic options.

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Section: Discussioncontrasting

confidence: 89%

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Kozlova

Samoylenko

Drobot

et al. 2015

Molecular Carcinogenesis

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“…ATRA is capable of inhibiting cell proliferation, inducing cell cycle arrest and cell differentiation (30)(31)(32)(33)(34). Dysregulation of FOXO1 expression has been observed to decrease the sensitivity of various carcinoma cells to differentiation and apoptosis inducers (24,26,(35)(36)(37).…”

Section: Upregulation Of Foxo1 By Atra or 5-fu Is Dependent On Qkimentioning

confidence: 99%

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Jin

Yang

et al. 2013

Oncology Reports

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The RNA-binding protein Quaking (QKI) is known to be essential for embryonic development and postnatal myelination. Forkhead box O1 (FOXO1) is a critical tumor suppressor for cell proliferation control. Dysregulation of FOXO1 expression has been observed in a variety of cancers. In the present study, we demonstrated that QKI decreased FOXO1 mRNA expression at the post-transcriptional level. QKI was able to bind the 3'UTR of FOXO1 mRNA directly and decreased its mRNA stability. To determine whether QKI-mediated post-transcriptional repression of FOXO1 indeed plays a role in cancer cells, we first detected both QKI and FOXO1 expression in four breast cancer cell lines. FOXO1 expression was extremely low in these cell lines, whereas QKI expression was relative high. Knockdown of QKI significantly restored FOXO1 expression. ATRA, an inducer of apoptosis or differentiation, dramatically enhanced FOXO1 expression while it repressed QKI expression. Importantly, the ATRA-induced increase in FOXO1 expression was dependent on QKI-mediated post-transcriptional regulation. Consistently, 5-FU, a widely used chemotherapeutic agent, increased FOXO1 expression via inhibition of QKI. In summary, our study provides initial evidence demonstrating that QKI-mediated repression of FOXO1 may be one of the factors contributing to the oncogenesis and progression of breast carcinoma, which suggests that targeting QKI may serve as a novel strategy to sensitize breast cancers to chemotherapy.

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“…Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Lung cancer can be histologically classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and the latter subtype constitutes 80% of lung cancers.…”

Section: Introductionmentioning

confidence: 99%

“…Among all NSCLC patients, about 25% are estimated to harbor “activating mutations” in sequences encoding the epidermal growth factor receptor (EGFR) that causes a constitutive activation of the EGFR signaling pathway and thus provides tumor cells with an increased abnormal growth advantage. In order to target this abnormal hyperactivation, selective agents such as EGFR tyrosine kinase inhibitors (TKIs) had been developed, some of which, including gefitinib and erlotinib, had been approved by FDA for treatment of NSCLC [1]. This type of drugs selectively bind to the ATP binding pocket of the phosphorylation sites on the EGFR tyrosine kinase domain, thus suppress EGFR activation and block downstream signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells

Chang

et al. 2013

Oncotarget

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Hyperactivation of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase is prevalent in human lung cancer and its inhibition by the tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, initially controls tumor growth. However, most patients ultimately relapse due to the development of drug resistance. In this study, we have discovered a STAT3-dependent Akt activation that impairs the efficacy of gefitinib. Mechanistically, gefitinib increased association of EGFR with STAT3, which de-repressed STAT3 from SOCS3, an upstream suppressor of STAT3. Such a de-repression of STAT3 in turn fostered Akt activation. Genetic or pharmacological inhibition of STAT3 abrogated Akt activation and combined gefitinib with STAT3 inhibition synergistically reduced the growth of the tumor cells. Taken together, this study suggests that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs in lung cancer.

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EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D₃in acute myeloid leukemia cells

Cited by 39 publications

References 62 publications

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells

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EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D3in acute myeloid leukemia cells

Cited by 39 publications

References 62 publications

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Urokinase is a negative modulator of Egf‐dependent proliferation and motility in the two breast cancer cell lines MCF‐7 and MDA‐MB‐231

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells

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EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D₃in acute myeloid leukemia cells