Aberrant expression of redox protein Ape1 in colon cancer stem cells

Abstract

Ape1 is an important redox protein, essential for specific cytokine-induced signal transduction. Ape1 signaling is also important in regulating the growth of cancer cells, including colon cancer cells. The present study investigated whether Ape1 signaling plays a role in the regulation of colon cancer stem cell (CCSC) growth. The results showed that Ape1 was aberrantly expressed in CCSCs, as determined by quantitative (q)PCR assay. A laser confocal microscopy assay demonstrated that the Ape1 protein was mainly distributed in the nuclei, but not the cytoplasm, of the CSCs. Treatment of CCSCs with Ape1 redox inhibitor (E3330) significantly affected growth in vitro. In colon cancer xenograft mice, in vivo administration of E3330 enhanced tumor responses to the chemotherapeutic drug, 5-fluorouracil (5-FU). Furthermore, the combination of E3330 and 5-FU evidently increased the cytotoxicity of 5-FU in CSC growth. In the qPCR assay, the CCSCs were demonstrated to express the dominant ATP-binding cassette sub-family G member 2 (ABC-G2), but not the multidrug resistance 1, genes. Thus, we hypothesized that drug resistance in CCSCs is mediated by ABC-G2. Since CSCs are involved in cancer metastasis, the Ape1 inhibitor may be a potential agent in the inhibition of colon cancer growth and metastasis.

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…Combining APE1‐targeted agents with 5‐FU in tumors genetically similar to Pa02C should respond favorably to this combination due to reduced BCRP expression. A study in colon cancer stem cells indeed demonstrated dramatically increased cell killing when 5‐FU and an inhibitor of APE1, APX3330, were used in vivo (Lou et al ., 2014). …”

“…APE1 expression is increased in several cancers such as pancreatic (Jiang et al ., 2010), prostate (Kelley et al ., 2001), cervical (Xu et al ., 1997), gliomas (Bobola et al ., 2004), lung (Yoo et al ., 2008), bladder (Shin et al ., 2015), colon (Lou et al ., 2014), and ovarian cancers (Al‐Attar et al ., 2010; Zhang et al ., 2009), and this increase is associated with resistance to radiation and chemotherapy, leading to poorer patient prognosis (Sharbeen et al ., 2015). Based on its involvement in cancer, and its regulation of several transcription factors associated with cancer‐related pathways, APE1 has become a prime target for anticancer therapies (Fishel and Kelley, 2007; Kelley et al ., 2014).…”

Oxidative Stress Promotes Doxorubicin‐Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions

“…APE-1 has been linked to resistance to alkylating agents, such as temozolomide, in glioblastoma cells [Silber et al, 2002]. In addition, E3330 treatment has been found to sensitize colon cancer stem cells to 5-fluoruracil therapy, indicating that this inhibitor may play an important role in reducing chemoresistance [Lou et al, 2014]. In this study, cells treated with doxorubicin þ Co exhibited diminished HIF-1a activity following E3330 administration.…”

Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

“…To assess the antiangiogenic activity of APX3330, the mice were i.p. injected with compound (50 mg/kg body weight), twice daily, five days on/two days off, as used previously in vivo (Fishel et al, 2011;Lou et al, 2014;Biswas et al, 2015). Vehicle was 4% Cremophor:ethanol (1:1) in PBS.…”