ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα

Abstract

Gliomas are resistant to radiation therapy, as well as to TNFα induced killing. Radiation-induced TNFα triggers Nuclear factor κB (NFκB)-mediated radioresistance. As inhibition of NFκB activation sensitizes glioma cells to TNFα-induced apoptosis, we investigated whether TNFα modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFα enhanced the ability of NCS to induce glioma cell apoptosis. NCS-mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFκB, Akt and Erk activation. Abrogation of Akt and NFκB activation further potentiated the death inducing ability of NCS in TNFα cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IκB abrogated NCS-induced TIGAR both in the presence and absence of TNFα, TIGAR had no effect on NFκB activation. Transfection with TIGAR mutant (i) decreased apoptosis and γH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFα. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFκB independent manner, ATM inhibition abrogated TIGAR and NFκB activation. Metabolic gene profiling indicated that TNFα affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM-NFκB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFα cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death.

TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia

“…As suppressing glycolysis with inhibitors was not effective at killing tumor cells, its combination with other tumor-specific metabolic inhibitors may be necessary for therapeutic intervention [32]. Silencing TIGAR also enhanced the radiosensitivity of U87MC and glioma cells [13]. Our findings suggest that combining glycolytic inhibitors with a potential TIGAR inhibitor and current standard chemotherapy may be a powerful and effective treatment for not only human leukemia but also other cancer types.…”

“…A number of genetic alterations seen in CN-AML patients with possible prognostic relevance (DNMT3A, IDH1/2, TET2) are not considered here, and the correlation of TIGAR expression and outcome may not be independent of other variables in CN-AML. In addition, TIGAR knockdown enhanced the radiosensitivity of cancer cells, suggesting that correlation of TIGAR expression and outcome of patients with CN-AML may also depend on the response of AML cells to chemotherapy [13]. In the future, it will be important to understand how TIGAR affects the response of leukemia cells to chemotherapy or targeted therapy.…”

“…On the other hand, TIGAR inhibited glycolysis through Fru-2,6-P2 degradation, directing metabolism into the pentose phosphate pathway (PPP) to produce NADPH and glutathione (GSH) as anti-oxidants, and ribose-5-phosphate for nucleotide synthesis [10]. TIGAR also showed high expression among several cancer types, including human colon tumors [4], breast cancer [11, 12], and glioblastoma [13–15], which suggesting that upregulated TIGAR expression may support, rather than inhibit, cancer development [1]. High TIGAR expression correlated with the increased tumor survival/burden, while TIGAR depletion promoted the apoptosis rate of cancer cells [12, 16–18].…”

Chaetocin-induced ROS-mediated apoptosis involves ATM–YAP1 axis and JNK-dependent inhibition of glucose metabolism

“…12 Five housekeeping genes were included on the array (B2M, HPRT1, RPL13A, GAPDH and ACTB) to normalize the transcript levels. Results were analyzed as per user manual guidelines using integrated web-based software package for the PCR Array System (RT2 Profiler PCR Array Human Glucose Metabolism PAHS-006Z).…”

Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory

“…However, navigation of the role of altered ATM gene in brain tumors seems to be too limited and has been restricted to few types of tumors such as glioma. In the recent study, the molecular mechanisms behind the resistance to radiotherapy were explored in glioma cells [14]. It was found that ATM expression plays important role in radioadaptive nature of glioma cells in cooperation with a network of other prosurvival proteins.…”