Elevated Prx1 Provides Resistance to Docetaxel, But Is Not Associated with Predictive Significance in Lung Cancer

Abstract

BackgroundThis study was conducted in order to elucidate the effects of docetaxel on the growth of peroxiredoxin 1 (Prx1) knockdown A549 xenograft tumors and further tested the role of Prx1 as a predictor for how a patient would respond to docetaxel treatment.MethodsEffects of docetaxel on the growth of scrambled- and shPrx1-infected A549 xenograft tumors in nude mice were measured. Moreover, immunohistochemical expression of Prx1 was evaluated in paraffin-embedded tissues from 24 non-small cell lung cancer patients who had received docetaxel-cisplatin regimens as a first-line treatment.ResultsDocetaxel treatment in Prx1 knockdown xenograft tumor resulted in reduced tumors growth compared with other groups. Prx1 knockdown increased the production of cleaved caspases-8 and -9 in the control itself compared to scramble tumors. Moreover, docetaxel treatment in Prx1 knockdown tissue led to an increased protein band. Phosphorylated Akt was found in Prx1 scramble tissues. Phosphorylated FOXO1 was detected in the docetaxel treatment group. On the other hand, Prx1 knockdown completely suppressed the Akt-FOXO1 axis. The median progression-free survival (PFS) of patients with low Prx1 expression was 7 months (95% confidence interval [CI], 6.0-7.7), whereas the median progression-free survival of patients with high Prx1 expression was 4 months (95% CI, 4.0-5.0). However, high Prx1 expression was not associated with decreased PFS (p=0.114).ConclusionOur findings suggest that elevated Prx1 provides resistance to docetaxel treatment through suppression of FOXO1-induced apoptosis in A549 xenograft tumors, but may not be related with the predictive significance for response to docetaxel treatment.

Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains

“…The overexpression of GSS was in human colorectal cancer cell lines and tissues compared with normal samples [ 32 ]. PRDX1 was identified as a tumor-associated antigen in esophageal squamous cell carcinoma [ 33 ] and acted via mTOR/p70S6K pathway [ 34 ]; its overexpression was demonstrated in multiple myeloma [ 35 ], was associated with tumour angiogenesis and progression in human hepatocellular cancer [ 36 ], provided resistance to docetaxel treatment of lung cancer [ 37 ] and to alkylating agent bis-chloroethyl nitroso urea of oligodendroglial tumors [ 38 ]. Increased CAT levels were found in patients with non-small cell lung cancer compared to controls [ 39 , 40 ].…”

Peroxiredoxin 1 – an antioxidant enzyme in cancer

“…PRDX1 also suppresses drug/radiation-induced cytotoxicity in lung cancer, and the related mechanisms are under investigation [25,83]. PRDX1 knockdown evokes an increase in cellular apoptotic potential through activation of the caspase cascade and suppression docetaxelinduced phosphorylation of Akt and its substrate FOXO1 in A549 xenograft tumours [83,84]. In addition, PRDX1 suppresses JNK activation through an indirect interaction with JNK in a peroxidase-independent manner [25].…”

Expression of thioredoxin 1 and peroxiredoxins in squamous cervical carcinoma and its predictive role in NACT

“…High levels of Prx 1 and Prx 2 correlated with cisplatin chemoresistance in gastric cancer SNU638 cells [27], in human erythroleukemia K652, in human breast cancer MCF-7 cells [28], and in human ovarian carcinoma SKOV-3 cells [28], as increased levels of this antioxidant inhibited apoptosis. Elevated Prx 1 induced resistance to docetaxel treatment through suppression of FOXO1-induced apoptosis in lung cancer A549 xenograft tumors [29]. Furthermore, in gastric carcinoma cells, Prx 2-specific antisense vectors restored the induction of pro-apoptotic pathways following cisplatin treatment, confirming the important role of Prx 2 in the resistance process [30].…”