The effect of 15-lipoxygenase-1 (15-LOX-1) on angiogenesis in colorectal and prostate cancer

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Tezin Türü: Yüksek Lisans

Tezin Yürütüldüğü Kurum: Orta Doğu Teknik Üniversitesi, Fen Edebiyat Fakültesi, Biyolojik Bilimler Bölümü, Türkiye

Tezin Onay Tarihi: 2017

Öğrenci: MELİS ÇOLAKOĞLU

Danışman: SREEPARNA BANERJEE

Özet:

15-lipoxygenase-1 (15-LOX-1) is one of the lipoxygenases (LOX) that are important for the generation of inflammatory bioactive lipids, which then result in the initiation and resolution of inflammation. The enzyme mainly metabolizes the omega-6 fatty acid, linoleic acid, to 13-(S)-HODE. In colorectal carcinoma, the tumor suppressive role of 15-LOX-1 is highlighted with decreased proliferation, induction of apoptosis, reduced motility and invasion. Oppositely, the expression of 15-LOX-1 was reported to have pro-carcinogenic role in prostate cancer. The effect of 15-LOX-1 expression on angiogenesis in cancer, however, has not been addressed adequately. Therefore, we investigated the expression and secretion of Vascular Endothelial Growth Factor-A (VEGF-A), which acts as a potent vascular permeability factor in the angiogenesis process, in response to 15-LOX-1 expression. We used the colon cancer cell line HCT-116 and prostate cancer cell lines PC-3 and LNCaP as our models. We observed a decreased expression of VEGF-A through decreased transcriptional activity of Hypoxia-Inducible Factor 1α (HIF-1α) along with decreased secretion in 15-LOX-1 expressing HCT-116 cells. Contrary to our expectations, we observed a similar reduction in the expression and secretion of VEGF-A in LNCaP cells but no change in PC-3 cells when these cells were transfected with a 15-LOX-1 vector. To find out 15-LOX-1 mediated signaling mechanisms in angiogenesis, a proteome profiler array was conducted with proteins isolated from Human Umbilical Vein Endothelial Cells (HUVECs) incubated with conditioned media collected from 15-LOX-1 overexpressing LNCaP cells and tissue inhibitor of metalloproteases (TIMP-1) was enriched. Enhanced expression of this anti-angiogenic protein may contribute towards the anti-angiogenic role of 15-LOX-1 in our prostate cancer model. Collectively, this study indicates the anti-tumorigenic and anti-angiogenic roles of 15-LOX-1 both in colorectal and prostate cancer.