p53-Regulated hexokinase 1b is a novel target for metabolic theraphy against non-small-cell lung cancer
Year: 2019
Type: dissertation
Abstract: Deregulation of glycolysis is common in non-small cell lung cancer (NSCLC). p53 controls the cellular metabolism pathway by activating hexokinases (HKs) to increase glycolysis. HK enzymes catalyze the phosphoryl-group-transfer in glucose metabolism. Unlike HK2, HK1 has several transcript variants. However, the functional differential roles of HK1 isoforms in glucose metabolism and the malignant tumor progression are still elusive. Here, we show that primary NSCLC patient tumor cells metabolically differ from the normal lung epithelium in that they display predominant expression of one of the HK1 isoforms, hexokinase1b (HK1b). Interestingly, we show that p53 positively regulates HK1b expression using CRISPR-Cas9 system. We utilized CRISPR-Cas9 system to selectively target specific HK1b isoform in NSCLC and show that silencing HK1b in NSCLC cells inhibits tumorigenesis through diminishing glycolysis and proliferation. Finally, HK1b deletion sensitizes NCLC cells to cisplatin treatment and the combination therapy synergistically increases both the p53- mediated apoptotic cell death by cisplatin and autophagic cell death by increased formation of LC3-II associated autophagic vesicles and myelinoid bodies in an AMPK-independent manner. Our findings reveal that targeting HK1b isoform alone or in combination with cisplatin may represent a novel strategy for NSCLC patients
Source: Sabanci University
Author: Yasemin Yozgat
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3169474342