Highlights d Antioxidants stimulate KRAS-driven lung cancer metastasis d Antioxidants reduce free heme levels and stabilize BACH1 d BACH1 activates Hk2 and Gapdh transcription triggering glycolysis-induced metastasis d Targeting BACH1 or its glycolytic targets prevents antioxidant-induced metastasis

Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.

Senescence is involved in various pathophysiological conditions. Besides loss of retinoblastoma and p53 pathways, little is known about other pathways involved in senescence. Here we identify two calcium channels; inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) (also known as inositol 1,4,5-triphosphate receptor 2 (IP3R2)) and mitochondrial calcium uniporter (MCU) as new senescence regulators in a loss-of-function genetic screen. We show that loss of ITPR2, known to mediate endoplasmic reticulum (ER) calcium release, as well as loss of MCU, necessary for mitochondrial calcium uptake, enable escape from oncogene-induced senescence (OIS). During OIS, ITPR2 triggers calcium release from the ER, followed by mitochondrial calcium accumulation through MCU channels. Mitochondrial calcium accumulation leads to a subsequent decrease in mitochondrial membrane potential, reactive oxygen species accumulation and senescence. This ER-mitochondria calcium transport is not restricted to OIS, but is also involved in replicative senescence. Our results show a functional role of calcium release by the ITPR2 channel and its subsequent accumulation in the mitochondria.

The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. Here we show that histone H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. H2A.J also accumulates in mice with aging in a tissue-specific manner and in human skin. Knock-down of H2A.J inhibits the expression of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over expression of H2A.J increases the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signalling of senescent cells to the immune system, and it may contribute to chronic inflammation and the development of aging-associated diseases.

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Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling. Cancer Res; 73(20); 6334-45. Ó2013 AACR.

Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant “Gemcitabine-based chemotherapy” benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.