CLDN6-induced apoptosis via regulating ASK1-p38/JNK signaling in breast cancer MCF-7 cells

Abstract

Claudin 6 (CLDN6), a member of tight junction protein claudin (CLDN) family, inhibits proliferation and induces apoptosis of MCF-7 breast cancer cells. However, these molecular mechanisms of CLDN6-induced apoptosis remain largely elusive. We previously found that restoration of human CLDN6 gene expression was correlated with the expression level of apoptosis signal-regulating kinase 1 (ASK1) using cDNA array and bioinformatics analysis. ASK1, a mitogen-activated protein kinase kinase kinase, is involved in environmental stress-activation of the c-jun N-terminal kinase (JNK) and p38 pathways, which contribute to apoptosis-associated tumor cell death. In the present study, we show that the restoration of CLDN6 gene expression in MCF-7 cells marhedly decreased ASK1 phosphorylation at Ser967. Activated ASK1ser967 further induced the activation of downstream targets, JNK and p38 kinase. MCF-7/CLDN6 stable transfection cell clone treated with TRX1, an ASK1 inhibitor, showed suppressed JNK and p38 activation, and showed substantially increased survival and colony formation and reduced percent of apoptotic cells using TUNEL staining and DNA ladder. Furthermore, TRX1 treatment increased Bcl-2/Bax ratio and reduced caspase-3 cleavage in MCF-7/CLDN6 stable transfection cell clone. Therefore, these data show that CLDN6 mediates ASK1-p38/JNK apoptotic signaling in MCF-7 cells, and it is correlated with constitutive deregulation of the balance of Bcl-2 family proteins and activation of caspase-3.

Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells

“…Phosphorylation of p38 during cell death has been reported on a number of occasions [56][57][58][59][60]. Furthermore, several research teams have shown p38 activation is linked with caspase-independent cell death mediated by the nuclear translocation of AIF [56,59,61,62].…”

Claudin 10 acts as a novel biomarker for the prognosis of patients with ovarian cancer

“…Tight junctions could be disrupted or 'loosened' in cancer cells in order to induce dissemination and migration during the cancer metastatic process. Therefore, claudins, including CLDN1, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN14 and CLDN17, serve a critical role in modulating carcinogenesis and metastasis (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). In a previous study, CLDN10 was reported to suppress cell metastasis by phosphorylating the Janus kinase 1/signaling transducer and activator of transcription 1 signaling pathway in osteosarcoma cells (38).…”

Key microRNAs in the biology of breast cancer; emerging evidence in the last decade

“…Interestingly, it was observed that miR‐655 suppresses EMT via targeting Prrx1 in triple‐negative BC (Lv et al, ). Also, very recently it was identified that claudins (CLDN6) inhibits the malignant progression and induces apoptosis in mammary tumor cells via the p38/MAPK pathway and ASK1 signaling, respectively (Guo et al, ; Q. Wu et al, ).…”