• Title/Summary/Keyword: PTEN

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Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy

  • Islamian, Jalil Pirayesh;Aghaee, Fahimeh;Farajollahi, Alireza;Baradaran, Behzad;Fazel, Mona
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.18
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    • pp.8431-8438
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    • 2016
  • Doxorubicin (DOX) was introduced as an effective chemotherapeutic for a wide range of cancers but with some severe side effects especially on myocardia. 2-Deoxy-D-glucose (2DG) enhances the damage caused by chemotherapeutics and ionizing radiation (IR) selectively in cancer cells. We have studied the effects of $1{\mu}M$ DOX and $500{\mu}M$ 2DG on radiation induced cell death, apoptosis and also on the expression levels of p53 and PTEN genes in T47D and SKBR3 breast cancer cells irradiated with 100, 150 and 200 cGy x-rays. DOX and 2DG treatments resulted in altered radiation-induced expression levels of p53 and PTEN genes in T47D as well as SKBR3 cells. In addition, the combination along with IR decreased the viability of both cell lines. The radiobiological parameter (D0) of T47D cells treated with 2DG/DOX and IR was 140 cGy compared to 160 cGy obtained with IR alone. The same parameters for SKBR3 cell lines were calculated as 120 and 140 cGy, respectively. The sensitivity enhancement ratios (SERs) for the combined chemo-radiotherapy on T47D and SKBR3 cell lines were 1.14 and 1.16, respectively. According to the obtained results, the combination treatment may use as an effective targeted treatment of breast cancer either by reducing the single modality treatment side effects.

Circulating Tumor DNA in a Breast Cancer Patient's Plasma Represents Driver Alterations in the Tumor Tissue

  • Lee, Jieun;Cho, Sung-Min;Kim, Min Sung;Lee, Sug Hyung;Chung, Yeun-Jun;Jung, Seung-Hyun
    • Genomics & Informatics
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    • v.15 no.1
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    • pp.48-50
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    • 2017
  • Tumor tissues from biopsies or surgery are major sources for the next generation sequencing (NGS) study, but these procedures are invasive and have limitation to overcome intratumor heterogeneity. Recent studies have shown that driver alterations in tumor tissues can be detected by liquid biopsy which is a less invasive technique capable of both capturing the tumor heterogeneity and overcoming the difficulty in tissue sampling. However, it is still unclear whether the driver alterations in liquid biopsy can be detected by targeted NGS and how those related to the tissue biopsy. In this study, we performed whole-exome sequencing for a breast cancer tissue and identified PTEN p.H259fs*7 frameshift mutation. In the plasma DNA (liquid biopsy) analysis by targeted NGS, the same variant initially identified in the tumor tissue was also detected with low variant allele frequency. This mutation was subsequently validated by digital polymerase chain reaction in liquid biopsy. Our result confirm that driver alterations identified in the tumor tissue were detected in liquid biopsy by targeted NGS as well, and suggest that a higher depth of sequencing coverage is needed for detection of genomic alterations in a liquid biopsy.

Roles of mTOR and p-mTOR in Gastrointestinal Stromal Tumors

  • Li, Jun-Chuan;Zhu, Hong-Yu;Chen, Ting-Xuan;Zou, Lan-Ying;Wang, Xiao-Yan;Zhao, Hui-Chuan;Xu, Jun
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.10
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    • pp.5925-5928
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    • 2013
  • Objective: This study aimed to examine the relationship between expression of mammal target of rapamycin (mTOR) and phosphorylation of mTOR (p-mTOR) protein in the PI3K/Akt/mTOR signaling pathways in gastrointestinal stromal tumors and relatiuonships with clinical factors. Methods: Immunohistochemistry was used to detect the expression of the associated proteins mTOR, p-mTOR, and phosphorylation of the tumor suppressor genes PTEN, P27, VEGF, and EGFR in 40 cases of gastrointestinal stromal tumors, with division into a very low and low risk group as well as a moderate and high risk group. Results: The positive rate of mTOR and p-mTOR was significantly increased in the moderate and high risk group compared with the very low and low risk group. The difference was statistically significant (P<0.05). When grouped according to size, the positive mTOR expression rate exhibited a statistical difference (P<0.05), which was significantly increased in the group of tumors larger than 5 cm. The difference in the positive mTOR and p-mTOR expression rate exhibit no statistical significance among the PTEN, P27, VEGF, and EGFR expression subgroups (P>0.05). Conclusion: The different expressions of mTOR and p-mTOR in the signal transduction pathway of gastrointestinal stromal tumor in the different degree-of-risk groups suggested that the mTOR and p-mTOR of the signal transduction pathway serve an important function in the occurrence and development of gastrointestinal stromal tumors.

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3'3-diindolylmethane suppresses esophageal cancer tumorigenesis

  • Ruo Yu Meng;Cong Shan Li;Dan Hu;Soon-Gu Kwon;Hua Jin;Ok Hee Chai;Ju-Seog Lee;Soo Mi Kim
    • The Korean Journal of Physiology and Pharmacology
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    • v.27 no.5
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    • pp.493-511
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    • 2023
  • Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3'3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

The Effects of Mistletoe Extract and Anti-cancer Drugs on the Apoptosis of Gastric Cancer Cells (위암세포 사멸에 미치는 겨우살이 추출물과 항암제의 효과)

  • Lee, Yong-Jik;Heo, Su Hak;Shin, Dong Gue;Kang, Sung-Koo;Kim, Il Myung;Kim, Tae Hee
    • Journal of Gastric Cancer
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    • v.8 no.3
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    • pp.120-128
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    • 2008
  • Purpose: Mistletoe extract was widely used for cancer treatment as complementary or alternative therapy in European area from early twenty century. It is currently used as alternative anti-cancer remedy by piecemeal in domestic medical group, however, the anti-cancer mechanism of mistletoe extract was not known precisely until now. In this study the effect of mistletoe extract on gastric cancer was studied vis cell line experiments. Materials and Methods: The SNU719 gastric cancer cell line was used, and ABNOBAviscum-Q and ABNOBAviscum-F were treated to cells as mistletoe extract, or 5-FU and cisplatin were used with mistletoe extract. The cell viability and cell death rate were estimated by CCK-8 assay kit and lactate dehydrogenase (LDH) assay kit in each. Caspase 3 assay kit was used to measure caspase 3 activity. The protein expression amounts of Bcl2, p53, and PTEN were estimated through Western blot analysis. Results: The co-treatments of mistletoe extract Q/F and 5-FU/cisplatin decreased lesser cell viability than only mistletoe treat. Caspase 3 activity was increased 4~6 times in co-treatment of mistletoe extracts and 5-FU than control. Bcl2 protein expression was reduced by mistletoe extracts or anti-cancer drugs, further more, the co-treatment of mistletoe extracts and 5-FU/cisplatin diminished more the expression than only mistletoe treatment. Mistletoe extracts did not affect the protein expressions of p53 and PTEN. Conclusion: It was concluded that the anti-cancer mechanism of mistletoe extracts was made by caspase 3 activation and lowered Bcl2 expression, and this apoptosis inducing mechanism was independent to p53.

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APOPTOTIC EFFECT IN COMBINATION OF CYCLOSPORIN A AND TAXOL ON ORAL SQUAMOUS CELL CARCINOMA CELL LINE THROUGH THE PI-3 KINASE/AKT1 PATHWAY (구강 편평세포암종 세포주에서 Cyclosporin A와 Taxol 투여시 PI-3 kinase/Akt1 Pathway에 의한 세포사멸 병용효과)

  • Kim, Kyu-Young;Lee, Jae-Hoon
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.33 no.5
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    • pp.426-436
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    • 2007
  • Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.

Inhibition of protein tyrosine phosphatase non-receptor type 2 by PTP inhibitor XIX: Its role as a multiphosphatase inhibitor

  • Le, Hien Thi Thu;Cho, Young-Chang;Cho, Sayeon
    • BMB Reports
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    • v.50 no.6
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    • pp.329-334
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    • 2017
  • Protein tyrosine phosphatases (PTPs) play crucial roles in signal transduction and their functional alteration has been detected in many diseases. PTP inhibitors have been developed as therapeutic drugs for diseases that are related to the activity of PTPs. In this study, PTP inhibitor XIX, an inhibitor of CD45 and PTEN, was investigated whether it inhibits other PTPs. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was selectively inhibited by the inhibitor in a competitive manner. Drug affinity responsive target stability (DARTS) analysis showed that the inhibitor induces conformational changes in PTPN2. Phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) at Tyr-705, a crucial site for STAT3 activation and target site of PTPN2, decreased upon exposure to the inhibitor. Our results suggest that PTP inhibitor XIX might be considered as an effective regulator of PTPN2 for treating diseases related to PTPN2.

Tankyrase: Function and Tankyrase Inhibitor in Cancer

  • Kim, Mi Kyung
    • Biomedical Science Letters
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    • v.24 no.3
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    • pp.150-156
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    • 2018
  • Tankyrases are multifunctional poly (ADP-ribose) polymerases that regulate a variety of cellular processes including WNT signaling, telomere maintenance, regulation of mitosis, and many others. Tankyrases interact with target proteins and regulate their interactions and stability through poly (ADP-ribosyl) ation. In addition to their roles in telomere maintenance and regulation of mitosis, tankyrase proteins regulate tumor suppressors such as AXIN, PTEN, and AMOT. Therefore, tankyrases can be effective targets for cancer treatment. Tankyrase inhibitors could affect a variety of pathways that are carcinogenic (essential for the unlimited proliferation of human cancer cells), including WNT, AKT, YAP, telomere maintenance, and regulation of mitosis. Recently, new aspects of the function and mechanism of tankyrases have been reported and several tankyrase inhibitors have been identified. Also, it has been proposed that the combination of conventional chemotherapy agents with tankyrase inhibitors may have synergistic anti-cancer effects. Based on this, it is expected that more advanced and improved tankyrase inhibitors will be developed, enabling new therapeutic strategies against cancer and other tankyrase linked diseases. This review discusses tankyrase function and the role of tankyrase inhibitors in the treatment of cancer.

Snail Switches 5-FU-induced Apoptosis to Necrosis through Akt/PKB Activation and p53 Down-regulation (Snail의 Akt/PKB의 활성화와 p53의 downregulation를 통한 5-FU-induced apoptosis의 necrosis로의 전환)

  • Lee, Su-Yeon;Jeon, Hyun-Min;Ju, Min-Kyung;Kim, Cho-Hee;Jeong, Eui-Kyong;Park, Hye-Gyeong;Kang, Ho-Sung
    • Journal of Life Science
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    • v.22 no.8
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    • pp.1018-1023
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    • 2012
  • Snail is a zinc finger transcription factor that induces epithelial-to-mesenchymal transition (EMT), which promotes tumor invasion and metastasis by repressing E-cadherin expression. In addition, Snail restricts the cellular apoptotic response to apoptotic stimuli or survival factor withdrawal; however, its molecular mechanism remains largely unknown. In this study, we have investigated the mechanism underlying Snail-mediated chemoresistance to 5-fluorouracil (5-FU), one of the most widely used anti-cancer drugs. When Snail was overexpressed by doxycycline (DOX) in MCF-7 #5 cells, it inhibited 5-FU-induced apoptotic cell death and switched the cell death mode to necrosis. Snail expression, either by DOX treatment in MCF-7 #5 cells or by the transfection of Snail expression vectors pCR3.1-Snail-Flg, phosphorylation-resistant pCR3.1-S104, and 107A Snail-Flg in MCF-7 cells specifically induced PTEN down-regulation/inactivation and Akt/PKB activation, without affecting ERK1/2 activity. In addition, Snail prominently suppressed 5-FU-induced increases in p53 levels. These findings demonstrate that Snail switches 5-FU-induced apoptosis to necrosis through the activation of Akt/PKB and the down-regulation of p53 levels.

IDENTIFICATION OF GENES INVOLVED IN OSTEOCLAST DIFFERENTIATION BY CDNA ARRAY ANALYSES (dDNA array를 이용한 파골세포 분화 관련 유전자의 탐색)

  • Cho, Young-Jun;Lee, Zang-Hee;Lee, Chang-Seop;Lee, Sang-Ho
    • Journal of the korean academy of Pediatric Dentistry
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    • v.29 no.2
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    • pp.278-284
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    • 2002
  • To examine the global gene expression of osteoclastogenesis-related genes in RAW 264.7 and its differentiated OCLs through the use of Atlas Mouse cDNA Array 2.1 membranes printed with 1176 well-characterized mouse genes involved in biology. Both samples were screened in parallel using cDNA expression arrays. The array results were additionally validated using RT-PCR. The results of cDNA arrays showed that 6 genes were up-regulated >2.5-fold (PKC beta II. POMC, PTEN, etc) and 16 genes were down-regulated >2.5-fold (Osteopontin, Cyclin D1, Cathepsin C, PTMA, etc) in both samples at the mRNA level. RT-PCR analysis of PKC beta II of these differentially expressed genes gave result consistent with cDNA array findings. The result of osteoclastogenesis showed that the PKC beta II gene was overexpressed in OCLs compared with RAW264.7 cell line. Osteoclastogenesis-related genes are differentially expressed in RAW264.7 cell line and its differentiated OCLs. its gene overexpression correlates with osteoclast differentiation in RAW264.7 cell line.

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