The phospholipase A2 activity of peroxiredoxin 6 promotes cancer cell death induced by tumor necrosis factor alpha in hepatocellular carcinoma

Abstract

In this study, we used proteomic profiling to compare hepatocellular carcinoma (HCC) and peri-tumoral tissues to identify potential tumor markers of HCC. We identified eight differentially expressed proteins (>3-fold), including Peroxiredoxin 6 (PRDX6). PRDX6 is a bifunctional enzyme with both peroxidase and calcium-independent phospholipase A2 (iPLA2) activity. We found that peri-tumoral tissues expressed higher levels of PRDX6 mRNA (n = 59, P = 0.018) and protein (n = 265, P < 0.001) than HCC tissues, and that decreased expression of PRDX6 in HCC tissues was an independent risk factor indicating a poor prognosis (n = 145, P = 0.007). Combining the examination of serum PRDX6 with α-fetoprotein improved the diagnostic sensitivity of tests for HCC compared to α-fetoprotein alone (85.0% vs 50.0%, n = 40). We found that PRDX6 induced S phase arrest in HCC cells and inhibited HCC tumorigenicity in mice injected with cancer cells. When treated with H2 O2 , PRDX6 inhibited apoptosis. When treated with tumor necrosis factor alpha (TNF-α), PRDX6 promoted apoptosis. Inhibition of iPLA2 activity of PRDX6 decreased the apoptosis induced by TNF-α. In conclusion, PRDX6 inhibited the carcinogenesis of HCC, and the iPLA2 activity of PRDX6 promoted cancer cell death induced by TNF-α. © 2015 Wiley Periodicals, Inc.

The phospholipase A2 activity of peroxiredoxin 6 [S]

“…Prdx6 prevented hyperglycemiamediated apoptosis in lens epithelial cells (137) and decreased apoptosis in tumors could support an increased rate of tumor growth. However, to the contrary, Prdx6 supported, rather than inhibited, TNFα-mediated apoptosis in hepatocellular carcinoma cells in vitro, and also in primary bronchial epithelial cells and a gastric cell line (123,128,138). This latter effect would tend to dampen rather than increase tumor growth and invasiveness as observed for Prdx6…”

“…Elevated expression levels for Prdx6 have been demonstrated in association with a broad variety of human cancers including lymphoma and cancer of the breast, esophagus, lung, liver, ovaries, pancreas, bladder, thyroid, gingiva, tongue, skin, and mesothelium among others (121)(122)(123)(124)(125)(126)(127)(128)(129)(130)(131)(132)(133).…”

“…Increased expression of Prdx6 correlated with a poorer prognosis for breast cancer and large Bcell lymphoma, progression of bladder cancer, and increased invasiveness of retinoblastomas (124,(133)(134)(135) but correlated with improved survival of patients with hepatocellular carcinoma (123) and some types of pancreatic adenocarcinoma (136). The correlation of Prdx6 expression with poor prognosis for breast cancer was associated with several single nucleotide On the other hand, a reasonable mechanism for increased tumor growth and invasiveness associated with Prdx6 overexpression has not been proposed.…”

“…Knockdown of presenilin 2 resulted in increased tumor growth in a mouse model of lung carcinoma; this effect was attributed to a secondary increase in aiPLA 2 activity, although the assay used to determine enzymatic activity was non-specific (139).The studies described above relating Prdx6 to apoptosis in hepatocellular carcinoma cells indicated that its PLA 2 activity was responsible for the effects (123); however that conclusion is suspect since it was based on the use of an inhibitor, bromoenol lactone (BEL), that does not inhibit aiPLA 2 activity (26,27,54). In a study of lung cancer cells, mutations S32A and C47S in Prdx6 both abolished the effect of wild type Prdx6 on tumor metastasis while MJ33 treatment had no effect (130);…”

The prognostic values of the peroxiredoxins family in ovarian cancer

“…Isohookana et al [23] reported that lack of cytoplasmic PRDX6 expression correlated with shorter disease-free survival in patients with larger pancreatic adenocarcinoma tumor size. Xu et al [69] found that PRDX6 was highly expressed in the peri-tumoral tissues and played a critical role in inhibiting the carcinogenesis of hepatocellular carcinoma. However, Yun et al [70,71] demonstrated that PRDX6 promoted the development of lung cancer via JAK2/STAT3 pathway, its GPx and iPLA2 activities.…”