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Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI–H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation. TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro . Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI–H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA. Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).

The effect of a cold treatment on the carbohydrate status of the scales and flower stalk of Tulipa gesneriana 1. cv Apeldoorn bulbs during growth after planting was studied and compared with bulbs not given cold treatment. Bulbs were stored dry for 12 weeks at 5'C (precooled) or 17°C (noncooled). Only the 5°C treatment led to rapid flower stalk elongation and flowering following planting at higher temperatures. Precooling enhanced mobilization of starch, fructans, and sucrose in the scales. The cold-stimulated starch breakdown was initially accompanied by increased a-amylase activity per scale. In noncooled bulbs, a-amylase activity slightly decreased or remained more or less constant. Cold-induced flower stalk elongation was partially accompanied by a decrease in the sucrose content and an increase in the glucose content and invertase activity per g dry weight. The starch content in internodes initially decreased and subsequently increased; a-amylase activity per g dry weight of the lowermost internode showed a peak pattern during starch breakdown and increased thereafter. The internodes of noncooled bulbs, on the contrary, accumulated sucrose. Their glucose content and invertase activity per g dry weight remained low. Starch breakdown was not found and a-amylase activity per g dry weight of the lowermost internode remained at a low level. Precooling of tulip bulbs thus favors reserve mobilization in the scales and flower stalk and glucose accumulation in the elongating internodes.It is well known that temperature controls the flowering process in many bulbous crops (Rees, 1972;De Hertogh and Le Nard, 1993). In the flowering process of tulips three phases have been distinguished: (a) the initiation phase, during which cell division and differentiation of the apical bud occur, resulting in the formation of a11 flower parts; (b) the preparation phase, during which the flower parts grow slowly and during which the conditions required for optimal flowering are prepared; and (c) the elongation phase, during which rapid extension growth of the shoot and flowering take place.In a temperate climate, flower initiation, flowering preparation, and shoot elongation occur in summer, winter, and spring, respectively. When bulbs are forced to flower at an earlier time, the cold winter period can be replaced by a welldefined, low-temperature treatment given to bulbs that are stored in climate rooms (dry-stored) (Rees, 1972;De Hertogh and Le Nard, 1993). Tulipa gesneriana L. cv Apeldoom bulbs require a dry-storage period of 12 weeks after planting at 5OC for optimal shoot elongation and flowering. The shoots of noncooled bulbs (dry-stored at 17OC) elongate slowly and, if anthesis is achieved, severe flowering disorders occur (Lambrechts et al., 1992).Experiments with exogenously applied GAs, GA biosynthesis inhibitors, and auxins showed that both GAs -and auxins are involved in the elongation process of the tulip flower stalk (Saniewski, 1989;Saniewski and Kawa-Miszczak, 1992). However, the sites of hormone action and the resu...

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