Blocking of PI3K/AKT induces apoptosis by its effect on NF-κB activity in gastric carcinoma cell line SGC7901

Xu, Chao; Zao, Jiang; Gu, Xing; Meng, Lingjun; Tao, Shi

doi:10.1016/j.biopha.2010.08.008

Cited by 40 publications

(34 citation statements)

References 25 publications

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“…PI3K/AKT pathway has been abnormally activated and closely associated with tumorigenesis and tumor progression [12]. AKT, a key regulator of cell survival and apoptosis has been associated with increased phosphorylation in a variety of cancers [33]. In the present context PI3K expression and phosphorylation at Tyr 508 was found up regulated in the oral cancer tissues which might have been influenced by increased phosphorylation of FAK Tyr 397.…”

Section: Discussionmentioning

confidence: 50%

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MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

Nanda¹,

Dutta²,

Ganguly³

et al. 2014

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Carcinoma of oral cavity have a high risk of recurrence after initial treatment with surgery, radiotherapy, surgery with adjuvant radiotherapy, or radio-chemotherapy.The present study investigated the changes in expression, activity and regulation of matrix metalloproteinases (MMP) -2 and -9 in oral squamous cell carcinoma (OSCC) which might help to ascertain the invasive potential of the tumor .Tumor tissues and adjacent normal tissues of OSCC patients [N,37; either sex; 20-70 yrs] were subjected to clinico-pathology, histopathology and TNM grading. The enzyme activity and associated signalling was observed with gelatin zymography, immunohistochemistry, ELISA, western blot and semi quantitative reverse transcriptase PCR.OSCC tissues were observed with elevated MMP-9 activity, enhanced expression of fibronectin (FN), phosphorylated focal adhesion kinase (FAK Try 397), phosphatidyl inositol 3-kinase (PI3K), protein kinase B (AKT) and reduced expression of tissue inhibitor of metalloproteinase-1(TIMP-1) than the control tissues.OSCC patients elicited a predominance of MMP-9 activity via up regulated FAK/PI3K/AKT pathway. A routine MMP-9 analysis may ascertain the invasiveness of the tumor and therefore may be professed as a suitable biomarker for metastatic potential of oral cancer. Key words: oral squamous cell carcinoma, MMP-9, zymography, eastern IndiaIn India, oral cancer forms a large group of malignancy representing 30-40% of all cancers [1]. By the year 2020 cancers of the mouth (64,525; 29.5%), tongue (38,052; 17.4%) and larynx (33,855,15.5%) will be the major sites of oral cancer [2].The frequency of oral malignancy varies between Indian states which might be due to regional differences in disease-specific risk factors [3]. The pattern of cancer incidence in rural West Bengal showed that the oral cavity, pharynx, larynx contributed to more than half of the cancers in men and about a quarter in women. Indigenous habits of chewing and smoking seemed to be primarily responsible for their high incidence [4].Oral squamous cell carcinoma (OSCC) is one of the deadliest forms of oral malignancy which is associated with high morbidity and mortality, resulting from local, regional and distant metastasis [5]. This creates a great concern for scientists and prioritizes the search for suitable biomarker of oral cancer.Matrix metalloproteinases (MMPs) are the principal mediators for the degradation of extracellular matrix (ECM) components which take place during the invasion and metastasis [6,7]. MMPs are zinc dependent family of endopeptidases and the gelatinases, MMP-2 (Gelatinase A, 72 KDa) and MMP-9 (Gelatinase B 92 KDa), are the master molecules for the malignant phenotype because of their unique property to degrade type IV collagen, a major component of the basement membrane [8].The orchestra of signaling molecules associated with MMP regulation is highly complicated. In areas with basement membrane defects the invading carcinoma cells may come in contact with the abundant stromal fibronectin (FN) matrix. The 12...

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Section: Discussionmentioning

confidence: 50%

“…By the year 2020 cancers of the mouth (64,525; 29.5%), tongue (38,052; 17.4%) and larynx (33,855,15.5%) will be the major sites of oral cancer [2].…”

mentioning

confidence: 99%

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

Nanda¹,

Dutta²,

Ganguly³

et al. 2014

neo

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“…Previous studies had demonstrated that MDR1 expression was driven by the NF-κB pathway, using a common agonist known as the phorbol ester 12-O-tetradecanoyl-13-acetate (TPA) (28,29). Crosstalk between the PI3K/Akt pathway and NF-κB has been demonstrated; NF-κB expression can be downregulated by treatment with LY294002 (26,30), indicating that downregulation of MDR1 expression is mediated by inhibition of the PI3K/Akt pathway. Even so, the relationship between signal transduction pathways and P-gp expression is a complex process involving more than a single pathway, of which we have highlighted regulation by the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine

et al. 2013

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The phosphatidylinositol 3‑kinase (PI3K)/Akt signaling pathway plays a crucial role in tumorigenesis and tumor progression by promoting cell proliferation and inhibiting apoptosis, a process closely associated with multidrug resistance (MDR) of tumors. LY294002 is a commonly used pharmacological inhibitor that acts at the ATP‑binding site of the PI3K enzyme, selectively inhibiting the PI3K/Akt pathway. In the present study, we evaluated the effect of LY294002 on the chemosensitivity of gastric cancer cells to vincristine (VCR) in vitro and in vivo and investigated the possible underlying cellular mechanisms. The effect of LY294002 on cell viability, apoptosis induction and inhibition of tumor growth was analyzed using MTT and TUNEL assay in in vitro and in vivo models of gastric cancer. Intracellular accumulation of VCR was determined by high performance liquid chromatography. The activity of the PI3K/Akt pathway was evaluated by western blot analysis. Furthermore, reverse transcription PCR and immunohistochemistry were performed to determine the mRNA and protein expression levels of MDR1/ P-glycoprotein (P‑gp) and apoptosis‑related factors. We found that gastric cancer cells treated with LY294002 showed a significant inhibition of PI3K/Akt activity. The PI3K inhibitor LY294002 combined with VCR worked synergistically to promote growth inhibition, induce apoptosis and increase the intracellular drug accumulation in gastric cancer cell lines. Similarly, LY294002 could cooperate with VCR to reduce tumor growth in a gastric cancer model in vivo. Finally, LY294002 was able to decrease the expression of MDR1/P‑gp, Bcl‑2 and XIAP, and upregulate expression of Bax and caspase‑3, thereby enhancing chemosensitivity to VCR by inhibiting a drug pump and inducing apoptosis. These results suggested that the PI3K/Akt inhibitor LY294002 can enhance chemosensitivity of human gastric cancer to VCR. This preclinical evaluation of a rational combination of LY294002 and VCR may provide a new strategy to resolve the MDR of gastric cancer.

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“…First, NF-kB is constitutively activated in human gastric cancer tissue and is associated with tumor progression (5). Second, it promotes gastric cancer growth by inhibiting apoptosis (6). Third, NF-kB mediates the induction of mitogenic gene products such as cyclin D1, which is overexpressed in human gastric cancer tissue and is inversely correlated with poor prognosis and poor survival (7).…”

Section: Introductionmentioning

confidence: 99%

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

Manu

Shanmugam

Ramachandran

et al. 2012

Clinical Cancer Research

135

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Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether g-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.Experimental Design: The effect of g-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kB activation by DNAbinding assay, and gene expression by Western blotting. The effect of g-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.Results: g-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kB, and suppressed the NF-kBregulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of g-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and g-tocotrienol. As compared with vehicle control, g-tocotrienol also suppressed the NF-kB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.Conclusions: Overall our results show that g-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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Blocking of PI3K/AKT induces apoptosis by its effect on NF-κB activity in gastric carcinoma cell line SGC7901

Cited by 40 publications

References 25 publications

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

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Blocking of PI3K/AKT induces apoptosis by its effect on NF-κB activity in gastric carcinoma cell line SGC7901

Cited by 40 publications

References 25 publications

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

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MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India