Hexavalent Chromium (Cr(VI) induces malignant cell transformation in normal bronchial epithelial (BEAS-2B) cells. Cr(VI)-transformed cells exhibit increased level of antioxidants, are resistant to apoptosis, and are tumorigenic. RNAseq analysis in Cr(VI)-transformed cells showed that expression of transcripts associated with mitochondrial oxidative phosphorylation is reduced, and the expression of transcripts associated with pentose phosphate pathway, glycolysis, and glutaminolysis are increased. Sirtuin-3 (SIRT3) regulates mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. SIRT3 was upregulated and it positively regulated mitochondrial oxidative phosphorylation in Cr(VI)-transformed cells. Our results suggests that SIRT3 plays an important role in mitophagy deficiency of Cr(VI)-transformed cells. Furthermore, SIRT3 knockdown suppressed cell proliferation and tumorigenesis of Cr(VI)-transformed cells. Nrf2 is a transcription factor that regulates oxidative stress response. This study investigated the role of Nrf2 in regulating metabolic reprogramming in Cr(VI)-transformed cells. We observed that in Cr(VI)-transformed cells p-AMPKthr172 was increased, when compared to normal BEAS-2B cells. Additionally, Nrf2 knockdown reduced p-AMPKthr172. Our results suggest that Nrf2 regulated glycolytic shift via AMPK regulation of PFK1/PFK2 pathway. Furthermore, our results showed that Nrf2 constitutive activation in Cr(VI-transformed cells increased cell proliferation and tumorigenesis. Overall this dissertation demonstrated that Cr(VI)-transformed cells undergo metabolic reprogramming. We demonstrated that Nrf2 constitutive activation plays decisive role on metabolic reprogramming induction, and SIRT3 activation contributing to increased cancer cell proliferation and tumorigenesis.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:toxicology_etds-1025 |
| Date | 01 January 2019 |
| Creators | de Freitas Clementino, Marco Antonio |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Toxicology and Cancer Biology |
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