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

Li, Baijun; Wang, Zhiwei; Zhong, Yonglong; Lan, Jiao; Li, Xiangwei; Lin, Hui

doi:10.1007/s12032-015-0531-0

Cited by 38 publications

(32 citation statements)

References 33 publications

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“…These included two chemokine receptors (CCR), CCR9 and CCR2, which have been implicated in driving oncogenesis and shown to induce apoptosis when depleted in cancerous cells [28, 29], Testis expressed 14 (TEX14) that is a PLK1 regulated protein [30], as well as Wnt inhibitory factor 1 (WIF1), which antagonises Wnt signaling [31] and may therefore be important for the control of the pathway in ovarian cancer cells. In addition, Three enzymes with roles in metabolism were identified from the screen as causing a significant fold decrease in the number of mitotically arrested cells following paclitaxel treatment after their depletion, two of which were more directly linked to glycolysis; XYLB and PFKFB4.…”

Section: Resultsmentioning

confidence: 99%

Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells

et al. 2017

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Taxanes represent some of the most commonly used chemotherapeutic agents for ovarian cancer treatment. However, they are only effective in approximately 40% of patients. Novel therapeutic strategies are required to potentiate their effect and improve patient outcome. A hallmark of many cancers is the constitutive activation of the PI3K/AKT pathway, which drives cell survival and metabolism. We discovered a striking decrease in AKT activity coupled with a significant reduction in glucose 6-phosphate and ATP levels during mitotic arrest in the majority of ovarian cancer cell lines tested, indicating a potential metabolic vulnerability. A high-content siRNA screen to detect novel metabolic targets in mitotically arrested ovarian cancer cells identified the glycolytic enzyme PFKFB4. PFKFB4 depletion increased caspase 3/7 activity, and levels of reactive oxygen species only in mitotically arrested cells, and significantly enhanced mitotic cell death after paclitaxel treatment. Depletion of PFKFB3 demonstrated a similar phenotype. The observation that some ovarian cancer cells lose AKT activity during mitotic arrest and become vulnerable to metabolic targeting is a new concept in cancer therapy. Thus, combining mitotic-targeted therapies with glycolytic inhibitors may act to potentiate the effects of antimitotics in ovarian cancer through mitosis-specific cell death.

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Section: Resultsmentioning

confidence: 99%

Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells

et al. 2017

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“…Numerous previous studies have also studied the essential effects of CCR9 on the AKT signaling pathway and related diseases. Li and coworkers 29 found that compromised CCR9-CCL25 interactions promoted apoptosis in non-small cell lung cancer cells by activating phosphatidylinositol 3 kinase/AKT in vitro, which resulted in the upregulation of antiapoptotic proteins and downregulation of apoptotic proteins. In addition, the results of breast cancer-related research demonstrated that the CCR9-CCL25 axis activates cell survival signals through AKT and subsequent GSK3b inactivation.…”

Section: Discussionmentioning

confidence: 99%

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

Xu¹,

Mei

Liu³

et al. 2016

JAHA

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BackgroundMaladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C‐C motif chemokine receptor 9 (CCR9), a subfamily of the G protein–coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune‐related diseases. Recently, CCR9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR9 exerts in cardiac hypertrophy remain elusive.Methods and ResultsWe observed significantly increased CCR9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss‐ and gain‐of‐function experiments, we found that pressure overload–induced hypertrophy was greatly attenuated by CCR9 deficiency in cardiac‐specific CCR9 knockout mice, whereas CCR9 overexpression in cardiac‐specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen‐activated protein kinases between groups, whereas the phosphorylation of AKT/protein kinase B and downstream effectors significantly decreased in CCR9 knockout mice and increased in CCR9 transgenic mice after aortic binding surgery.ConclusionsThe prohypertrophic effects of CCR9 were not attributable to the mitogen‐activated protein kinase signaling pathway but rather to the AKT–mammalian target of rapamycin–glycogen synthase kinase 3β signaling cascade.

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“…This finding was consistent with our previous experimental result that CCR9 is up-regulated in NSCLC compared with adjacent normal lung tissue at the transcriptional level [ 10 ]. Previously, we have also shown that over-expressed CCR9 interacts with CCL25 to promote proliferation and suppress apoptosis of NSCLC cells in vitro , and knockdown of CCR9 compromises in vivo tumor growth in a nude mice model [ 11 ]. These observations demonstrated that like other members of the CC chemokine receptor family [ 13 ], CCR9 may function as an oncogene and play an important role in the tumorigenesis and development of lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we observed a clear trend between CCR9 expression and pathologic differentiation, although this trend was not significant (p = 0.225). In the previous study, we have found that CCR9-CCL25 axis plays a significant role in survival of NSCLC cells by inhibiting cancer cell apoptosis both in vitro and in vivio through the activation of PI3K/Akt signaling pathway, and cell survival is essential for cancer cells to achieve invasion and metastasis [ 11 ]. Therefore, over-expression of CCR9 in lung adenocarcinoma suggested its crucial role in disseminating primary tumor and promoting tumor cell survival during metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in our previous study, for the first time, we have shown the potential role of CCR9 in lung cancer, demonstrating that it is significantly over-expressed in tissues and cell lines from NSCLC, and CCR9-CCL25 axis promotes the migration and invasion capability of NSCLC cells in vitro [ 10 ]. Our subsequent study suggested that CCR9-CCL25 interaction supports lung cancer cell survival and up-regulates the anti-apoptotic signaling mediated by the PI3K/Akt survival pathway [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Expression of CC chemokine receptor 9 predicts poor prognosis in patients with lung adenocarcinoma

et al. 2015

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BackgroundThe CC chemokine receptor 9 (CCR9) plays an important role in tumorigenesis and metastasis in various cancers. Our previous studies have shown the aberrant expression of CCR9 in non-small cell lung cancer (NSCLC) cell lines, revealing that the CCR9-CCL25 axis modulates cell migration and invasion, and supports cancer cell survival by inhibiting apoptosis in vitro and in vivo. In the present study, we aimed to evaluate the expression and possible prognostic role of CCR9 in lung adenocarcinoma.MethodsImmunohistochemical analysis of CCR9 expression was performed on 144 lung adenocarcinoma tissues and 30 adjacent normal lung parenchymal tissues. We assessed the correlation of CCR9 expression with clinicopathological characteristics and the prognosis of lung adenocarcinoma.ResultsThe expression of CCR9 was increased in lung adenocarcinoma tissue compared with normal lung tissue. Moreover, such an expression was positively correlated with tumor size (p = 0.032), lymph node metastasis (p = 0.002) and advanced TNM stage (p = 0.012). In addition, the patients with negative CCR9 expression exhibited a higher overall survival (OS) compared with those with positive CCR9 expression. Multivariate analysis showed that the CCR9 expression was an independent prognostic factor for the OS of patients with lung adenocarcinoma.ConclusionsWe, for the first time, reported that CCR9 could be beneficial in predicting lymph node metastasis, and it might act as a novel prognostic biomarker for lung adenocarcinoma.

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

Cited by 38 publications

References 33 publications

Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells

Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

Expression of CC chemokine receptor 9 predicts poor prognosis in patients with lung adenocarcinoma

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