DRP1 promotes lactate utilization in KRAS-mutant non-small-cell lung cancer cells.

Metabolic alterations are well documented in various cancers. Non-small-cell lung cancers (NSCLCs) preferentially use lactate as the primary carbon source, but the underlying mechanisms are not well understood. We developed a lactate-dependent cell proliferation assay and found that dynamin-related protein (DRP1), which is highly expressed in KRAS-mutant NSCLC, is required for tumor cells to proliferate and uses lactate as fuel, demonstrating the critical role of DRP1 in the metabolic reprogramming of NSCLC. Metabolic and transcriptional profiling suggests that DRP1 orchestrates a supportive metabolic network to promote lactate utilization and redox homeostasis in lung cancer cells. DRP1 suppresses the production of reactive oxygen species (ROS) and protects cells against oxidative damage by enhancing lactate utilization. Moreover, targeting DRP1 not only reduces HSP90 expression but also enhances ROS-induced HSP90 cleavage, thus inhibiting activation of mitogen activated protein kinase and PI3K pathways and leading to suppressed lactate utilization and increased ROS-induced cell death. Taken together, these results suggest that DRP1 is a crucial regulator of lactate metabolism and redox homeostasis in KRAS-mutant lung cancer, and that targeting lactate utilization by modulating DRP1 activity might be an effective treatment for lung cancer.

Di-(2-ethylhexyl)-phthalate interferes with T-follicular helper cell differentiation and cytokine secretion through signaling lymphocytic activation molecule family member-1.

Exposure to the widely-used phthalate plasticizer di-(2-ethylhexyl)-phthalate (DEHP) has been shown to be closely related to an increased prevalence of allergic diseases in infants and juveniles. Earlier work in our laboratory found that DEHP-related anaphylactic responses could be ascribed to T-follicular helper (Tfh) cell hyperfunction directly. The Tfh cell, a newly identified CD4+ TH cell subset, until recently has been considered as a key player in humoral immunity. Tfh cells can respond to stimulation through various receptors. Signaling lymphocytic activation molecule family member-1 (SLAMF1, CD150) is a surface co-stimulatory receptor that can bind to an intracytoplasmic adaptor signaling lymphocytic activation molecule-associated protein (SAP) to initiate downstream signaling cascades, regulating some events of immune response. The present study explored the role of SLAMF1 in Tfh cell differentiation and cytokine secretion under the condition of DEHP exposure. Using a weanling mice model of DEHP gavage with ovalbumin (OVA) sensitization, it was found that DEHP acted as an immunoadjuvant to elevate SLAMF1 and SAP expression in host Tfh cells. Ex vivo studies of effects from DEHP exposure on Tfh cells from OVA-sensitized hosts showed that DEHP acted in an adjuvant-like manner to promote the expression of adaptor protein SAP, transcription factors Bcl-6 and c-MAF, and cytokines interleukin (IL)-21 and IL-4 in Tfh cells. Transfection of these Tfh cells with Slamf1 small interfering RNA prior to exposure to the DEHP attenuated the over-expression of these molecules that was caused by the DEHP. In conclusion, this study demonstrated that DEHP, via a SLAMF1-mediated pathway, can impact on Tfh cell differentiation and their ability to form select cytokines.