DeRossi, C. et al. Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality.

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA-damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the down-regulation of inhibitor of apoptosis (IAP) proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy.

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.

The occurrence of peritoneal carcinomatosis is a major cause of treatment failure in colorectal cancer and is considered incurable. However, new therapeutic approaches have been proposed, including cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Although HIPEC has been effective in selected patients, it is not known how HIPEC prolongs a patient's lifespan. Here, we have demonstrated that HIPEC-treated tumor cells induce the activation of tumor-specific T cells and lead to vaccination against tumor cells in mice. We have established that this effect results from the HIPEC-mediated exposure of heat shock protein (HSP) 90 at the plasma membrane. Inhibition or blocking of HSP90, but not HSP70, prevented the HIPEC-mediated antitumoral vaccination. Our work raises the possibility that the HIPEC procedure not only kills tumor cells but also induces an efficient anticancer immune response, therefore opening new opportunities for cancer treatment.

SummarySensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.

Key Points Caloric restriction reduces Mcl-1 expression and sensitizes lymphoma cells to ABT-737 in vivo. Caloric restriction mimetics can sensitize lymphomas to ABT-737–induced death independently of p53 and of the main BH3-only proteins.