Molecular Imaging Reveals a Role for AKT in Resistance to Cisplatin for Ovarian Endometrioid Adenocarcinoma

Wang, Hanxiao; Galbán, Stefanie; Wu, Rong; Bowman, Brittany M.; Witte, Amanda; Vetter, K.; Galbán, Craig J.; Ross, Brian D.; Cho, Kathleen R.; Rehemtulla, Alnawaz

doi:10.1158/1078-0432.ccr-12-2380

Cited by 17 publications

(17 citation statements)

References 40 publications

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“…Further it has been reported that activation of the PI3K/ Akt pathway is involved in acquired resistance (Sunters et al, 2003;Zhong et al, 2010;Wang et al, 2013). Observations of our study showed significantly upregulation of PTEN with markedly down-regulated expression of Akt, mTOR and p-GSK3β.…”

Section: Discussionsupporting

confidence: 65%

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

Xin

2015

Bangladesh J Pharmacol

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<p class="Abstract">Despite advances in conventional therapies, treatment of prostate cancer is still a challenge. The study aims to assess the possible anti-cancer effects of tangeretin, a dietary flavonoid on human prostate cancer cells (DU145, PC3, LNCaP). Tangeretin (25, 50 and 100 µM) significantly inhibited cancer cell viability and induced DNA fragmentation and apoptosis by increasing caspase-3 and pro-apoptotic proteins (Bad and Bax) with reduced anti-apoptotic proteins (Bcl-2 and Bcl-xL) expressions. Significant inhibition of androgen receptor (AR) and prostate specific antigen (PSA) were seen. Dose-dependent inhibition in Notch signal was observed in expression of Notch 1 and Jagged 1 along with PI3/Akt/mTOR signalling pathway. The results suggest that tangeretin inhibited prostate cancer cell proliferation and induced apoptosis via inhibiting critical pathways in cancer development - AR signalling and PI3/Akt/mTOR - Notch signalling pathways.</p><p> </p>

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Section: Discussionsupporting

confidence: 65%

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

Xin

2015

Bangladesh J Pharmacol

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“…Similar to previous reports (19), relatively lower doses of drugs, that is, 2.5 mg/kg DDP or 5 mg/kg Taxol, were given via the tail vein after the tumor diameters reached 0.5 cm, and the drugs were administered once every 4 days. Similar to the results obtained in vitro, the silencing of CABYR-a/b alone significantly delayed tumor growth and decreased the total weight of the tumors in H460 xenografts compared with control animals, and these inhibitory effects were increased when the mice were treated with DDP or Taxol.…”

Section: Cabyr-a/b Knockdown Increases Tumor Sensitivity To Ddp and Tmentioning

confidence: 89%

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Qian

Wang

et al. 2014

Molecular Cancer Research

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CABYR is a calcium-binding tyrosine phosphorylation-regulated protein that was identified as a novel cancer testis antigen in lung cancer in our previous study. However, the role of CABYR as a driver of disease progression or as a chemosensitizer is poorly understood. This study sought to investigate the relationship between the expression levels of CABYR-a/b, which are the two predominant isoforms of the five isoform proteins encoded by CABYR, and chemosensitivity in non-small cell lung cancer cells. We found that the short hairpin RNA-mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. The silencing of CABYR-a/b expression notably impacted the downstream components of the Akt pathways: decreasing the phospho-GSK-3b (Ser9) levels and increasing the expression of the p53 and p27 proteins. Furthermore, CABYR-a/b knockdown led to a significant increase in chemosensitivity in response to chemotherapeutic drugs and drug-induced apoptosis, both in vitro and in vivo. Conversely, the transient transfection of CABYR-a/b-depleted cells with constitutively active Akt partially restored the resistance to cisplatin and paclitaxel and significantly decreased the activation of GSK-3b and cleaved PARP. Taken together, our results suggest that the inhibition of CABYR-a/b is a novel method to improve the apoptotic response and chemosensitivity in lung cancer and that this cancer testis antigen is an attractive target for lung cancer drug development.

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“…Murine ovarian endometrioid adenocarcinoma cell lines were derived as previously described (18). Briefly, the W2476T tumor cell line was established by mechanically dispersing ovarian tumor tissues with sterile scalpels followed by digestion at 37° C with 0.05% Trypsin-EDTA for 20 minutes.…”

Section: Methodsmentioning

confidence: 99%

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

Burgos-Ojeda

McLean

et al. 2015

Molecular Cancer Therapeutics

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Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, inter-patient variability and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers including CD24, CD44, CD90, CD117, CD133 and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells vs CD24− cells, had significantly greater tumor initiation and tumor growth capacity. No preferential tumor initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared to CD24− cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

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Molecular Imaging Reveals a Role for AKT in Resistance to Cisplatin for Ovarian Endometrioid Adenocarcinoma

Cited by 17 publications

References 40 publications

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

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