Regulation and Novel Action of Thymidine Phosphorylase in Non-Small Cell Lung Cancer: Crosstalk with Nrf2 and HO-1

Abstract

Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.

Proapoptotic effects of heme oxygenase-1 inhibitor on Kasumi-1 cells via the ATF4/CHOP/Ire-1α pathway

“…Cells generate a defensive, protective response against external environmental stimuli by inducing HO-1 expression (Wang et al, 2014a), making HO-1 a potential promoting factor for the growth of lung cancer, liver cancer, malignant glioma, and other tumor cells (Zou et al, 2011;Tertil et al, 2014). We previously reported that inducing HO-1 expression by hemin elevated the survival rate of chronic myelocytic leukemia cells, indicating that HO-1 and the survival of such cells were closely associated.…”

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

“…Induction of VEGF expression by CO is linked to the activation of hypoxia inducible factor-1 (HIF-1α) [57], the effect which might be also responsible for the synthesis of transforming growth factor-β (TGF-β) [58]. The role of other proangiogenic enzyme, thymidine phosphorylase in HO-1 mediated angiogenesis has been also suggested [59,60].…”

Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases

“…NCI-H292 cell lines overexpressing NFE2L2 or HMOX1 were developed earlier in our laboratory as described in [14] and [9], respectively.…”