FK506 Accelerates CoCl2 - Induced Cytotoxicity via Endoplasmic Reticulum Stress Pathway in HepG2 Cells

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Abstract

Background

The effects of FK506 on the endoplasmic reticulum (ER) mediated stress pathway accelerates CoCl2 - induced cytotoxicity in human hepatoma HepG2 cell line were investigated.

Methods

We examined the effects of FK506 on CoCl2 - induced cytotoxicity by western blottings of poly ADP-ribose polymerase(PARP), CHOP, GRP78, Nrf2, ATF4, ATF6, XBP-1, Bak, Bax, and Bcl-2. And the catalytic acitivity of caspase-3 and -12 caspase in HepG2 cells was also measured.

Results

FK506 and CoCl2 significantly induces the synergistic effect of HepG2 cytotoxicity in dose dependent manner. Increased active-PARP expression occurred at 24 hours after FK506 treatment on CoCl2-induced HepG2 cytotoxicity and peak activation of cleaved caspasec-3 was also observed at 24 hours. FK506 aggravates CoCl2-induced HepG2 cytotoxicity. GRP78 expression was increased 24 hours after FK506 treatment on CoCl2-induced HepG2 cytotoxicity. CHOP and caspase-12 expressions were increased 24 hours after FK506 treatment on CoCl2-induced HepG2 cytotoxicity. Expressions of ATF4 and ATF6 were same manners. Expression of XBP-1 was decreased beginning at 6 hours. FK506 exasperate endoplasmic reticulum stress by CoCl2-induced cytotoxicity. Bcl-2 protein expression decreased, but FK506 induces expression of Bak and Bax by CoCl2 induced cytotoxicity. Nrf2 expression was also noted.

Conclusions

FK506 and CoCl2 significantly induces the synergistic effect of cytotoxicity in dose dependent manner. FK506 aggravates CoCl2-induced cytotoxicity. FK506 exasperate endoplasmic reticulum stress by CoCl2 -induced cytotoxicity. FK506 accelerates expression of ER-stress related nuclear transcriptional factor.

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