title: Nuclear translocation of telomerase reverse transcriptase and calcium signaling in repression of telomerase activity in human lung cancer cells by fungal immunomodulatory protein from Ganoderma tsugae.
abstract: Recombinant fungal immunomodulatory protein, reFIP-gts, was cloned from Ganoderma tsugae and purified. In our previous study, it was shown that reFIP-gts has anti-telomerase effects in A549 cells. Here, we proved that reFIP-gts entry into the cell and localization in endoplasmic reticulum can result in ER stress, thereby increasing ER stress markers (CHOP/GADD153) and intracellular calcium release in A549 cells. The use of calcium chelator restores reFIP-gts-mediated reduction in telomerase activity. These results strongly suggest that ER stress induces intracellular calcium release and results in inhibition of telomerase activity. Although reFIP-gts decreased hTERT mRNA level in both A549 and H1299 cells, only the telomerase activity in A549 cells was inhibited. Surprisingly, we found that reFIP-gts induces translocation of hTERT from the nucleus into the cytosol in A549 cells but not in H1299 cells. Using leptomycin B, nuclear export inhibitor, we showed that hTERT is not transported. Using MG132, a proteasome inhibitor, reFIP-gts also prevents hTERT translocation from proteasome degradation. Taken together, these results indicate that reFIP-gts inhibits telomerase activity in lung cancer cells through nuclear export mechanisms, which might be mediated by ER stress-induced intracellular calcium level.
authors.affiliation: Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Liao
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Hsiao
authors.forename: Gwo-Tarng
authors.initials: GT
authors.lastname: Sheu
authors.forename: Jinghua Tsai
authors.initials: JT
authors.lastname: Chang
authors.forename: Po-Hui
authors.initials: PH
authors.lastname: Wang
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.forename: Gow-Jen
authors.initials: GJ
authors.lastname: Shieh
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Hsu
authors.forename: Jiunn-Liang
authors.initials: JL
authors.lastname: Ko
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005656:Fungal Proteins / Q000494:pharmacology*; D032902:Ganoderma; D006801:Humans; D037102:Lectins / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D037102:Lectins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase