Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway

Ni, Jie; Cozzi, Paul; Hao, Jingli; Beretov, Julia; Chang, Lei; Duan, Wei; Shigdar, Sarah; Delprado, Warick; Graham, Peter; Bucci, Joseph; Kearsley, John H.; Li, Yong

doi:10.1016/j.biocel.2013.09.008

Cited by 159 publications

(130 citation statements)

References 63 publications

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“…In many cancers, this signaling pathway is frequently activated and is essential for cancer invasion and metastasis [33][34][35]. It has been reported that EMT could be mediated by PI3K/AKT/mTOR pathway [36].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-495 suppresses osteosarcoma invasion and migration by targeting HSP90AA1

Xiao¹,

Wang²,

Li³

et al. 2018

Oncotarget

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MiR-495 is a tumor-suppressive microRNA that participates in tumor progression in human cancers. However, its expression and biological function in osteosarcoma remains unknown. In this study, we firstly found that miR-495 is markedly downregulated in both osteosarcoma tissues and cell lines. Then we demonstrated that miR-495 suppresses the invasion and metastasis of osteosarcoma cells in vitro through inhibiting epithelial to mesenchymal transition. Function of miR-495 in vivo was also examined in mice xenograft model and we found it significantly inhibiting the lung-metastasis of osteosarcoma cells. We also demonstrated that HSP90AA1 is a direct target of miR-495 using luciferase reporter assay and Western blot analysis. Furthermore, knockdown of HSP90AA1 can restore the increased cell invasion and migration in miR-495-knockdown cells and over expression of HSP90AA1 can neutralize the impaired metastatic ability of miR-495 mimic-treated cells. This metastasis-suppressive role of miR-495 in osteosarcoma is achieved by HSP90AA1-mediated PI3K/Akt/mTOR signaling pathway. Overall, our findings proved for the first time that miR-495 acts as a tumor suppressor in osteosarcoma and inhibits cell migration and invasion by targeting HSP90AA1, thus offering a promising therapeutic target for osteosarcoma treatment.www.impactjournals.com/oncotarget/

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Section: Discussionmentioning

confidence: 99%

MicroRNA-495 suppresses osteosarcoma invasion and migration by targeting HSP90AA1

Xiao¹,

Wang²,

Li³

et al. 2018

Oncotarget

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“…Previous studies established that the PI3K/AKT pathway is activated in numerous tumors, including breast cancers, pituitary adenoma and prostate cancer (10,13). An increasing number of studies have shown that the PI3K/AKT signaling pathway may modulate the expression of MMPs, as well as TIMPs, to promote the degradation of ECM proteins, and this mechanism was essential for invasion of human tumors, including lung cancer (13,23).…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of studies have shown that the PI3K/AKT signaling pathway may modulate the expression of MMPs, as well as TIMPs, to promote the degradation of ECM proteins, and this mechanism was essential for invasion of human tumors, including lung cancer (13,23). To the best of our knowledge, allicin has been confirmed to inhibit the PI3K/AKT signaling pathway in the HepG2 cell line; however, it remains unknown whether such an effect also exists in lung adenocarcinoma (17).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, activation of the PI3K/AKT signaling pathway was suggested to be associated with the invasion of numerous tumor types, including prostate, ovarian, colon and breast cancers (10)(11)(12)(13). In lung cancer, the PI3K/AKT signaling pathway is also considered as a crucial activator of intracellular signaling cascades in invasion progression and is useful as a therapeutic target for anticancer drug development.…”

Section: Introductionmentioning

confidence: 99%

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Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling

et al. 2017

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Abstract. Allicin, the main active principle associated with Allium sativum chemistry, has various antitumor activities. However, to the best of our knowledge, there is no available information to address the anti-invasive effect and associated mechanism in lung adenocarcinoma. In the present study, cell viability assay, cell adhesion assay, western blot analysis, Transwell migration and invasion assays and reverse transcription-quantitative polymerase chain reaction were performed. Allicin was identified to inhibit the adhesion, invasion and migration of lung adenocarcinoma cells in a dose-dependent manner, accompanied by decreasing mRNA and protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. Conversely, the mRNA and protein levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were increased in a dose-dependent manner. Furthermore, it was revealed that allicin treatment significantly suppressed the phosphorylation of AKT (P<0.05), but not the total protein expression of AKT. Combined treatment with LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K)/AKT signaling, and allicin led to the synergistic reduction of MMP-2 and MMP-9 expression, followed by an increase in TIMP-1 and TIMP-2 expression. The invasive capabilities of lung adenocarcinoma cells were also suppressed. However, insulin-like growth factor-1 (an activator of PI3K/AKT signaling) reversed the effects of allicin on cell invasion and expression of MMP-2, MMP-9, TIMP-1 and TIMP-2. The present study concluded that allicin may inhibit invasion of lung adenocarcinoma cells by altering TIMP/MMP balance, via reducing the activity of the PI3K/AKT signaling pathway. This indicated that allicin may be recognized as an anti-invasive agent for lung adenocarcinoma treatment. IntroductionLung cancer is the predominant reason of cancer-associated mortality in developed and developing countries. Lung adenocarcinoma is the most common histological type of lung cancer, and accounts for ~50% of all lung cancers (1). Although the management and treatment of surgery, radiotherapy and chemotherapy have improved, the therapeutic efficacy is poor. One of the major reasons is the lack of adequate treatment against lung adenocarcinoma invasion (2,3). Therefore, the development of novel adjuvant therapeutic strategies specifically targeting the progression of invasion is of critical importance for improving the prognosis of patients with lung adenocarcinoma.Invasion occurs through a complex pathophysiological process involving multiple genetic alterations (4,5). Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in the invasion process of numerous malignant tumors by degrading the basement membrane and extracellular matrix (ECM) (6-8). Previous studies have suggested that MMP-2 and MMP-9 are associated with invasion in lung cancer (4,5). In addition, numerous studies have demonstrated that MMPs may be regulated by tissue inhibitor of metalloproteinase (TIMP) (6,9). Disturbing the balance of MMPs and TIMPs ma...

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“…Recently, activation of the PI3K/Akt signaling pathway is associated with enhanced PC cell proliferation, invasion, metastasis, chemo-/radio-resistance, stemness and EMT, which would indicate that PI3K-targeting modalities could be a promising method to eliminate CSCs and to overcome treatment-resistance of PC. [36][37][38] In this study, we identified Tpl2 as a master regulator that controls the EMT and stemness of CRPC. Although Tpl2 protein kinase does not directly phosphorylate PI3K, PI3K is a downstream component of FAK/Akt and CXCL12/CXCR4 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Tpl2 induces castration resistant prostate cancer progression and metastasis

Lee

Cho

Lee

et al. 2014

Intl Journal of Cancer

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Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related deaths in males in the United States. 1 Although androgen depletion therapy is highly effective in suppressing PC growth, persistent androgen ablation often results in the development of metastatic castration resistant prostate cancer (CRPC). 2 Currently, patients with metastatic CRPC are treated with taxane-based chemotherapeutic drugs. However, the treatment only serves as a palliative, and distant metastasis is the main cause of PC-related death. 3 Therefore, the identification of novel therapeutic targets in metastatic CRPC is the most urgent clinical requirement that remains unmet.Tumors contain a reservoir of cancer stem cells (CSCs) that are responsible for tumor initiation, progression, metastasis and therapeutic resistance. 4 Since emerging evidence suggests that PC CSCs represent the "bad seeds" of tumor, the molecular mechanisms that maintain PC CSCs could potentially serve as therapeutic targets for metastatic CRPC. 5,6 Although aldehyde dehydrogenase (ALDH) activity 7 and expression of CD44 8 and Bmi-1 9 have been suggested as specific PC CSC markers, using these markers as therapeutic targets is challenging because the molecules lack specific functional and/or enzymatic activities.Tumor progression locus 2 [Tpl2/MAP3 kinase 8 (MAP3K8)], a serine/threonine protein kinase, has been suggested to enhance tumor growth and metastatic progression in distinct types of human cancers. 10-12 Previously, we

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Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway

Cited by 159 publications

References 63 publications

MicroRNA-495 suppresses osteosarcoma invasion and migration by targeting HSP90AA1

MicroRNA-495 suppresses osteosarcoma invasion and migration by targeting HSP90AA1

Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling

Tpl2 induces castration resistant prostate cancer progression and metastasis

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