The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment?

Crudden, Caitrin; Ilić, Marko; Suleymanova, Naida; Worrall, Claire; Girnita, Leonard

doi:10.1016/j.ghir.2014.10.002

Cited by 34 publications

(46 citation statements)

References 153 publications

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“…13, 36, 37, 38, 39, 40, 41 Following ligand stimulation, the adaptor protein β-arrestin 1 or -2 is recruited to the receptor C-terminal, mediating Mdm2 binding, receptor ubiquitination and degradation. 15, 42, 43 …”

Section: Resultsmentioning

confidence: 99%

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

et al. 2017

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Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: an early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain.

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Section: Resultsmentioning

confidence: 99%

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

et al. 2017

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“…Among these, the Ras/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway has been established (23). Novel treatments targeting the RSK, PI3K/Akt and MEK/ERK signaling pathways are currently under evaluation in numerous types of tumors in clinical trials (24)(25)(26). AML is an aggressive hematological disorder characterized by an abnormal increase of immature hematopoietic progenitor cells known as 'blasts', which lose their ability to differentiate normally and continue to proliferate.…”

Section: A B Discussionmentioning

confidence: 99%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

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Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

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“…The apoptosis of miCCR9 transfected cells increased significantly compared with the respective controls (*P \ 0.05) are members of GPCR family and are highly expressed in solid cancer cells. Recent studies have indicated that chemokine receptors may be involved in the regulation of tumorigenesis of cancer cells [19].…”

Section: Discussionmentioning

confidence: 99%

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

Wang

Zhong

et al. 2015

Med Oncol

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CC chemokine receptor-9 (CCR9) is highly expressed in non-small cell lung cancer (NSCLC) tissues and cell lines. However, the biological functions and the signals elicited by the interaction between CCR9 and its natural ligand CCL25 in NSCLC are unknown. Here, we selectively depleted CCR9 and inhibited CCR9-CCL25 interaction in NSCLC cells using small recombinant lentivirus-mediated miRNA, and investigated the tumorigenic effects in vitro and in vivo. Compromised CCR9-CCL25 interaction promoted apoptosis in NSCLC cells by activating phosphoinositide 3-kinase (PI3K)/Akt in vitro. In addition, we showed that CCR9-CCL25 interaction mediated the activation of the PI3K/Akt pathway in NSCLC cells, resulting in the up-regulation of anti-apoptotic proteins, as well as the down-regulation of apoptotic proteins in a PI3K-/Akt-dependent manner. These CCR9-CCL25-mediated effects were abrogated in the presence of a PI3K inhibitor (wortmannin 10 nM) or by inhibiting the CCR9-CCL25 interaction through CCR9 silencing, which also suggested that the biological function of CCR9-CCL25 was mainly regulated by PI3K. In vivo studies also demonstrated a significantly lower tumor burden in mice receiving CCR9-silence cells than those in mice receiving control cells. Together, these data suggested that CCR9-CCL25 interaction induced tumorigenesis of NSCLC cells and that this induction might be accomplished through the activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of CCR9-CCL25 interaction and provide clues for identifying novel therapeutic and preventive molecular markers for NSCLC.

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The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment?

Cited by 34 publications

References 153 publications

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

CCR9–CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway

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