Effects of gap junction intercellular communication on the docetaxel-induced cytotoxicity in rat hepatocytes
Nan Tang1, Jinghua Liu1, Bo Chen1
1School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China.
Abstract:
The effect of gap junction intercellular communication (GJIC) on docetaxel-induced hepatotoxicity and its underlying mechanisms are largely unknown. The present study involved investigating the effect of downregulating GJs derived from connexin (Cx) 32 in BRL-3A cells by three different mechanisms: Using a low-density culture; suppression of Cx32 using small interfering RNA; and use of the chemical inhibitor 2‑aminoethoxydiphenyl borate (2‑APB), all of which led to attenuated docetaxel hepatotoxicity. In order to investigate the relevant mechanisms involved, apoptosis and caspase activities of BRL‑3A cells were determined. The increase of apoptosis and the activation of caspase‑3 and caspase‑9, but not caspase-8, were detected following cell exposure with docetaxel, demonstrating that the mitochondrial‑mediated apoptosis pathway is largely responsible for docetaxel hepatotoxicity. However, reduced apoptosis and caspase‑3, and ‑9 activities were observed following docetaxel application when BRL‑3A GJIC was deficient from the knockdown of Cx32 expression or pretreatment with 2‑APB. These observations illustrate that GJs are important in docetaxel-induced hepatotoxicity. Furthermore, inhibition of GJIC could prevent amplification of toxicity to docetaxel. Due to GJIC blockage, this hepatoprotection was associated, in part, with decreasing apoptosis of BRL‑3A cells through the mitochondrial pathway. The present study provides evidence for potential therapeutic targets for the treatment of docetaxel-induced liver injury.
Insights
Gap junction intercellular communication (GJIC) plays a key role in docetaxel-induced liver injury. Inhibiting GJIC, particularly connexin 32, reduces docetaxel hepatotoxicity by decreasing mitochondrial-mediated apoptosis.
Area of Science:
- Hepatology
- Cell Biology
- Pharmacology
Background:
- Docetaxel is a widely used chemotherapy agent, but its use is limited by potential liver toxicity.
- The role of gap junction intercellular communication (GJIC) in docetaxel-induced hepatotoxicity remains largely unexplored.
- Connexin 32 (Cx32) is a key component of GJIC in liver cells.
Purpose of the Study:
- To investigate the effect of downregulating GJIC on docetaxel-induced hepatotoxicity in BRL-3A cells.
- To elucidate the underlying mechanisms of GJIC's involvement in docetaxel liver injury.
- To explore potential therapeutic strategies for mitigating docetaxel hepatotoxicity.
Main Methods:
- Downregulation of GJIC using low-density culture, Cx32 small interfering RNA (siRNA), and the chemical inhibitor 2-aminoethoxydiphenyl borate (2-APB).
- Assessment of docetaxel-induced hepatotoxicity, including apoptosis and caspase activities (caspase-3, -9, and -8).
- Analysis of the mitochondrial-mediated apoptosis pathway.
Main Results:
- Downregulation of GJIC significantly attenuated docetaxel-induced hepatotoxicity.
- Docetaxel exposure increased apoptosis and activated caspase-3 and -9, indicating mitochondrial pathway involvement.
- Inhibition of GJIC reduced docetaxel-induced apoptosis and caspase activation, thereby protecting against liver injury.
Conclusions:
- Gap junction communication, particularly involving Cx32, is crucial in mediating docetaxel-induced hepatotoxicity.
- Inhibiting GJIC offers a protective effect against docetaxel liver injury.
- Targeting GJIC presents a potential therapeutic avenue for managing docetaxel-induced liver damage.
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