Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells

Abstract

Metabolic alterations in cancer cells are primarily caused by oncogenic mutations and cancer cells are more dependent on glucose compared to non-transformed tissue. Targeting the cancer metabolism opens up a new strategy for anti-cancer therapy. In order to make drugs more efficient and applicable in the clinic, it is necessary to fully investigate the cancer cell metabolism, especially of how cancer cells die upon glucose deprivation and more importantly, the consequences on the surrounding tissue when modifying or interfering with the metabolism. The unfolded protein response (UPR) is an intracellular stress response which is induced upon glucose deprivation. The activation of the three branches of the UPR facilitates pro-survival responses, however, chronic exposure to intra- or extracellular stress results in a switch towards a pro-death UPR response. The UPR is also described to be involved in pro-inflammatory responses due to the induction of cytokines and chemokines in several cell lines. Therefore, the release of cytokines upon glucose deprivation could facilitate the infiltration or exclusion of immune cells. We hypothesized that cancer cells die in an UPR dependent manner and that cancer cells release inflammatory cytokines upon glucose deprivation, which promote the infiltration of immune cells. We found that HeLa cells exposed to glucose deprivation, died in a TRAIL receptor 1 (DR4) and 2 (DR5) dependent manner, which was mediated by the activation transcription factor 4 (ATF4). Furthermore, we found the release of pro-tumorigenic cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and the leukemia inhibitory factor (LIF) from glucose deprived cancer cells as well as upon treatment with anti-metabolic drugs. We found that IL 6 and IL-8 but not LIF were regulated by ATF4 and p65 upon glucose deprivation. Moreover, the conditioned media of glucose deprived A549 promoted the migration of macrophage-like THP-1 cells as well as primary B cells and neutrophils isolated from human blood. These findings are important, since interfering with the cancer metabolism by using anti metabolic drugs could suppress the anti-tumorigenic effect of these drugs by promote pro-tumorigenic responses.