Therapeutic strategy targeting the mTOR–HIF‐1α–VEGF pathway in ovarian clear cell adenocarcinoma

Miyazawa, Masaki; Yasuda, Masanori; Fujita, Mariko; Kajiwara, Hiroshi; Hirabayashi, Kenichi; Takekoshi, Susumu; Hirasawa, Takeshi; Murakami, Masaru; Ogane, Naoki; Kiguchi, Kazushige; Ishiwata, Isamu; Mikami, Mikio; Osamura, R. Yoshiyuki

doi:10.1111/j.1440-1827.2008.02320.x

Cited by 73 publications

(60 citation statements)

References 43 publications

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“…It is known that mutations of PIK3CA are common molecular genetic alterations identified in OCCC (11). Expression of phospho-mTOR was found to be more prominent in OCCC than in OSAC (22). mTOR exists in two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2.…”

Section: Discussionmentioning

confidence: 99%

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

et al. 2014

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Abstract.Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC 50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC 50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC 50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G 1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent. IntroductionClear cell carcinoma of the ovary (OCCC) is recognized in the World Health Organization classification of ovarian tumors as a distinct histological entity. Its clinical behavior is distinctly different from other epithelial ovarian cancers (1). OCCC accounts for 3.7-12.1% of epithelial ovarian cancers (2,3). We found that response rates for platinum-based chemotherapy were 11.1% for OCCC and 72.5% for serous adenocarcinoma (SAC), suggesting that OCCC resists conventional platinumbased chemotherapy (4). A novel therapeutic strategy is needed to improve the prognosis of patients with OCCC.PIK3CA is located at the 3q26.3 locus and encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K), p110α (5). In response to an extracellular signal, the activated p110α phosphorylates PIP2 to generate PIP3. The PIP3 recruits AKT to the plasma membrane, where it is phosphorylated and activated by phosphatidylinositol-dependent kinase 1 (PDK1) and PDK2. Activated AKT can directly activate the mammalian target of rapamycin (mTOR) by phosphorylation at Ser2448. mTOR ...

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Section: Discussionmentioning

confidence: 99%

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

et al. 2014

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“…This HIF-1α-mediated expression of VEGF may be an important mechanism regulating luteal development and function in the mammalian ovary. HIF-1α antagonism may be useful for the development of novel treatments for fertility control and for certain types of ovarian dysfunction (11,43,46), particularly those conditions characterized by pathological angiogenesis and excessive vascular permeability, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1, a helix-loop-helix transcriptional factor, which consists of HIF-1α and HIF-1β, has been cloned and characterized as a transcriptional activator of several oxygen-sensitive genes, including erythropoietin, heme oxygenases, transferrin and several glycolytic enzymes (27)(28)(29)40), whose protein products are important in developmental and physiological processes, including angiogenesis, erythropoiesis, glycolysis, iron transport and cell proliferation/survival (2,5,11,(41)(42)(43). It has been reported that HIF-1α protein is inducible by a decrease of O 2 concentration in tissue or cells.…”

Section: Discussionmentioning

confidence: 99%

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Zhang

Pan

et al. 2015

Mol Med Report

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Abstract. Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia-inducible factor (HIF)-1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF-1α is induced and then regulates the expression of VEGF and VEGF-dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small-molecule inhibitor of HIF-1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF-1α and VEGF by reverse transcription-quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF-1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF-1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF-1α-mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.

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“…In transgenic (orthotopic) and xenograft mouse models, treatment with the mTOR inhibitor everolimus delayed tumor development, reduced tumor burden, and prolonged survival (9)(10)(11)(12). mTOR inhibition reduced VEGF-A expression and diminished vascularization in murine (xenograft) ovarian cancers (9,10).…”

Section: Introductionmentioning

confidence: 99%

Measurement of Tumor VEGF-A Levels with 89Zr-Bevacizumab PET as an Early Biomarker for the Antiangiogenic Effect of Everolimus Treatment in an Ovarian Cancer Xenograft Model

Bilt

Scheltinga

Timmer‐Bosscha

et al. 2012

Clinical Cancer Research

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Purpose: The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with 89Zr-bevacizumab. Experimental Design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo89Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry. Results: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered 89Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUVmean) 2.3 ± 0.2 vs. 2.9 ± 0.2, P < 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 ± 0.8%ID/g vs. 14.0 ± 1.7%ID/g, P < 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01). Conclusion: Tumor VEGF-A levels are decreased by everolimus. 89Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy. Clin Cancer Res; 18(22); 6306–14. ©2012 AACR.

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Therapeutic strategy targeting the mTOR–HIF‐1α–VEGF pathway in ovarian clear cell adenocarcinoma

Cited by 73 publications

References 43 publications

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Measurement of Tumor VEGF-A Levels with 89Zr-Bevacizumab PET as an Early Biomarker for the Antiangiogenic Effect of Everolimus Treatment in an Ovarian Cancer Xenograft Model

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