T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

Abstract

We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

Construction and validation of a prognostic model for hepatocellular carcinoma: Inflammatory ferroptosis and mitochondrial metabolism indicate a poor prognosis

“…T cells may mediate cell death by various mechanisms. Previous studies have demonstrated that Th17 cells may activate and induce cell death by Fas-mediated apoptosis, which is consistent with our results ( 40 , 41 ).…”

The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa

“…They can activate caspases through a series of signal transduction, thus leading to the degradation of the nucleus and various substrates in the cytoplasm (32,33). Caspase-3 is the most common executor of the apoptosis pathway (34,35). The Bcl-2 family serves a critical role in regulating apoptosis, while ERK1/2 phosphorylation can achieve anti-apoptosis and promote proliferation through phosphorylating Bcl-2, activating transcriptional factors, and interfering TNF related apoptosis inducing ligand (36,37).…”

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

“…It has been suggested that a Warburg-like mechanism also is operative in other rapidly proliferating cells and tissues ( e.g. , T-lymphocytes, embryonic tissues) [23] , [24] .…”