In the tetrapyrrole biosynthetic pathway, isoforms of glutamyl-tRNA reductase (HEMA2) and ferrochelatase1 (FC1) are mainly expressed in nonphotosynthetic tissues. Here, using promoter-b-glucuronidase constructs, we showed that the expressions of Arabidopsis (Arabidopsis thaliana) HEMA2 (AtHEMA2) and FC1 (AtFC1) were induced in photosynthetic tissues by oxidative stresses such as wounding. Transcript levels and b-glucronidase activity were rapidly induced within 30 min, specifically in the wound area in a jasmonate-independent manner. Transcriptome analysis of wound-specific early inducible genes showed that AtHEMA2 and AtFC1 were coinduced with hemoproteins outside plastids, which are related to defense responses. Ozone fumigation or reagents generating reactive oxygen species induced the expression of both genes in photosynthetic tissues, suggesting that reactive oxygen species is involved in the induction. Since cycloheximide or puromycin induced the expression of both genes, inhibition of cytosolic protein synthesis is involved in the induction of these genes in photosynthetic tissues. The physiological functions of AtHEMA2 and AtFC1 were investigated using insertional knockout mutants of each gene. Heme contents of the roots of both mutants were about half of that of the respective wild types. In wild-type plants, heme contents were increased by ozone exposure. In both mutants, reduction of the ozone-induced increase in heme content was observed. These results suggest the existence of the tetrapyrrole biosynthetic pathway controlled by AtHEMA2 and AtFC1, which normally functions for heme biosynthesis in nonphotosynthetic tissues, but is induced in photosynthetic tissues under oxidative conditions to supply heme for defensive hemoproteins outside plastids.

Higher levels of FOLR1 appear to be associated with better prognoses for patients with lung adenocarcinomas.

BACKGROUND: The authors elucidated particular chemokine receptors that are expressed on lung cancer cells, as well as the clinical significance of the expression of these chemokine receptors in completely resected nonsmall cell lung cancer (NSCLC). METHODS: The authors examined gene expression of chemokine receptors (CCR1‐11, CXCR1‐7, XCR1, and CX3CR1) in 11 cell lines of lung cancer, and gene expression of CXCR3, CXCR4, and CXCR7 (CXCR3/4/7) in surgical specimens of 127 patients who underwent complete resection for their NSCLC between May 2001 and December 2002, using quantitative real‐time reverse transcriptase–polymerase chain reaction (PCR). Mutation detection analysis of the EGFR genes using the PCR single‐strand conformational polymorphism method was evaluated in patients with pathological (p‐) stage I adenocarcinoma. RESULTS: Substantial expression of CXCR3/4/7 mRNA was observed in all NSCLC cell lines examined. In p‐stage I NSCLC, CXCR4 and CXCR7 expression values in patients with postoperative metastatic recurrence (Rec‐Distant) were significantly higher than in those without recurrences (P = .003 and P = .007, respectively). In addition, the 5‐year disease‐free survival (DFS) rate of high CXCR7‐expressing patients (63.2%) was significantly lower than that of low CXCR7‐expressing patients (84.8%) (P = .033). The EGFR mutation was significantly more frequent in patients with higher CXCR7 expression (14 of 21 patients) than in those with lower CXCR7 expression (12 of 32 patients) (P = .038). A multivariate analysis confirmed that high CXCR7 expression was an independent and significant factor predicting a poor DFS in p‐stage I NSCLC patients (P = .041). CONCLUSIONS: Higher expression of CXCR7 is associated with Rec‐Distant and poor DFS in patients with p‐stage I NSCLC. Cancer 2009. © 2009 American Cancer Society.

Keap1 gene mutations are likely to be associated with a worse prognosis and lower postoperative disease-free survival rates in pathological Stage I-II NSCLC.

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Background: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299. Methods: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction. Results: MTA showed potent cytotoxicity against 211H cells (IC₅₀, 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results. Conclusion: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM.