Selective β2‐AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR‐Akt/ERK1/2 Signaling, G1‐Phase Arrest, and Apoptosis

Chin, Chih‐Chien; Li, Jhy-Ming; Lee, Kam-Fai; Huang, Yun‐Ching; Wang, Kuan-Chieh; Lai, Hsiao-Ching; Cheng, Chih-Chung; Kuo, Yi-Hung; Shi, Chung‐Sheng

doi:10.1002/jcp.25092

Cited by 62 publications

(39 citation statements)

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“…It was identified that the non-selective β-blocker propranolol and the selective β 2 -blocker ICI 118,551 significantly inhibited the viability of MDA-MB-231 cells, whereas the selective β 1 -blocker metoprolol did not. Similar results were reported by Chin et al (35), who identified that colorectal cancer cells were only sensitive to ICI 118,551 and propranolol, but not atenolol (a selective β 1 -blocker), and the effects of ICI 118,551 were the most potent. However, Liu et al (36) identified that atenolol and ICI 118,551 were able to attenuate the function of epinephrine in promoting esophageal cancer cell proliferation.…”

Section: Discussionsupporting

confidence: 89%

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

Xie

Zhang

et al. 2018

Oncol Rep

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The β 2 -adrenergic receptor (β 2 -AR, encoded by the ADRB2 gene) is a member of the G-protein-coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that β-blockers (β-AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single-nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of β 2 -AR, which may alter the β-blocker drug response. The aim of the present study was to investigate the effect of β-blockers on triple-negative breast cancer cells and determine whether ADRB2 SNPs affect the response to β-blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA-MB-231 cells, arrested cell cycle progression at G 0 /G 1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular-signal-regulated kinase (ERK)1/2 and the expression levels of cyclo-oxygenase 2 (COX-2) were significantly decreased following β-blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild-type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX-2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA-MB-231 cells by downregulating the ERK/COX-2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated. β-blockers inhibit the viability of breast cancer cells by regulatingthe ERK/COX-2 signaling pathway and the drug response is affected by ADRB2 single-nucleotide polymorphisms

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Section: Discussionsupporting

confidence: 89%

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

Xie

Zhang

et al. 2018

Oncol Rep

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“…Chin et al also investigated the effect of selective beta2-adrenergic receptor antagonists, including PRO, in a panel of colorectal cancer cells lines [57]. They showed that PRO significantly inhibited the viability of SW620, Colo205, and HT29 cells (IC50 119.5, 86.38, and 69.1 μM, respectively).…”

Section: Pre-clinical Evidence In Cancer - In Vitro and In Vivomentioning

confidence: 99%

“…The pro-apoptotic action of PRO was found to be via blockade of the beta2-adrenergic receptor rather than beta1, as shown by the increased level of apoptosis induced by the selective beta2 antagonist butaxamine and the reduced level due to the beta1 blocker metoprolol. Chin and colleagues also showed that in colorectal cancer cell lines PRO was associated with cell cycle arrest and apoptosis [57]. …”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Pantziarka

Bouche

Sukhatme³

et al. 2016

ecancer

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Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

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“…EGFR can interact with and activate various potential downstream signaling molecules and intracellular signal transduction pathways, thereby eliciting various cellular responses including proliferation, differentiation, and migration [13,14]. EGFR can be activated by mechanical stimuli.…”

Section: Introductionmentioning

confidence: 99%

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Shen

Gao

et al. 2016

Cell Physiol Biochem

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Background/Aims: The present study aimed to analyze the mechanisms by which periodic mechanical stress is translated into biochemical signals, and to verify the important role of signaling molecules including phosphatidylinositol-3-kinase (PI3K)-Akt, protein kinase C (PKC), and epidermal growth factor receptor (EGFR) in chondrocyte proliferation. The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress need further investigation. Methods: Two steps were undertaken in the experiment. In the first step, the cells were pretreated with shRNA targeted to Akt or EGFR or PKCδ or control scrambled shRNA. Moreover, they were pretreated with LY294002, GF109203X, Gö6976, rottlerin, and AG1478. They were maintained under static conditions or periodic mechanical stress for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. In the second step, the cells were pretreated with shRNA targeted to Akt or EGFR or PKCδ or control scrambled shRNA. Moreover, they were pretreated with LY294002, AG1478, and rottlerin. They were maintained under static conditions or periodic mechanical stress for 1 h prior to Western blot analysis. Results: Proliferation was inhibited by pretreatment with PKC or PKCδ inhibitor GF109203X or rottlerin and by short hairpin RNA (shRNA) targeted to PKCδ, but not by PKCα inhibitor Gö6976 in chondrocytes in response to periodic mechanical stress. Meantime, rottlerin and shRNA targeted to PKCδ also attenuated EGFR, Akt, and ERK1/2 activation. Furthermore, inhibiting EGFR activity by AG1478 and shRNA targeted to EGFR abrogated chondrocyte proliferation and phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK)1/2 subjected to periodic mechanical stress, while the phosphorylation site of PKCδ was not affected. In addition, pretreatment with the PI3K-Akt-selective inhibitor LY294002 and shRNA targeted to Akt reduced periodic mechanical stress-induced chondrocyte proliferation and phosphorylation of ERK1/2, while the phosphorylation levels of EGFR and PKCδ were not inhibited. Conclusion: These findings suggested that periodic mechanical stress promoted chondrocyte proliferation through PKCδ-EGFR-PI3K-Akt-ERK1/2. They provide a stronger viewpoint for further investigations into chondrocyte mechanobiology under periodic mechanical stress and the ways to improve the quality of tissue-engineered cartilage.

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Selective β2‐AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR‐Akt/ERK1/2 Signaling, G1‐Phase Arrest, and Apoptosis

Cited by 62 publications

References 50 publications

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

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