Abstract
This study compared the sensitivity of human hepatoma Hep3B, SK-HEP-1, SMMC-7721, and BEL-7402 cells to cardiac steroids, including bufalin (BF), a bufalin derivative (BF211), ouabain (OUA), and digitoxin (DIG). Hep3B cells exhibited relatively low sensitivity to cardiac steroids. Expression levels of subunits of Na+/K+-ATPase were high in Hep3B cells. However, colocalization of Na+/K+-ATPase and caveolin was nearly undetectable in Hep3B cells. By using RNA-Seq technology, we found a total of 36 genes to be differentially expressed between Hep3B cells and SK-HEP-1 cells, which are highly sensitive to cardiac steroids. Our bioinformatics analysis determined that these genes were mostly comprised of extracellular space, protein binding, and extracellular region. Among these 36 genes, apolipoprotein E (APOE) played a critical role, as knockdown APOE expression induced colocalization of Na+/K+-ATPase and caveolin and increased sensitivity of Hep3B cells to both proliferation-inhibiting and cytotoxic effects of BF or BF211. Also, the effects of BF on PI3K/AKT/GSK3β and apoptosis signal cascades were enhanced in APOE knockdown cells. The results of our study confirmed the role of Na+/K+-ATPase signalosome in cytotoxicity of cardiac steroids and suggested that APOE regulated the sensitivity of cells to cardiac steroids by affecting formation and function of Na+/K+-ATPase signalosome. In addition, intercellular interaction with high level of Na+/K+-ATPase β1 subunit may be also a factor in the low sensitivity of Hep3B cells to cardiac steroids. Mol Cancer Ther; 15(12); 2955-65. ©2016 AACR.
Highlights
Hepatocellular carcinoma is one of the most aggressive malignancies [1, 2]
To check whether Hep3B cells were resistant to all chemotherapy agents, we studied the sensitivity of Hep3B cells to cisplatin, a commonly used anticancer agent, and compared the results with SKHEP-1 cells which exhibited high sensitivity to cardiac steroids
These results suggested that the low sensitivity of Hep3B cells to cardiac steroids was not based on deficiency in cell death signaling and execution pathways but might be related to specific response to cardiac steroids
Summary
Hepatocellular carcinoma is one of the most aggressive malignancies [1, 2]. The percentage of patients benefited from surgical treatment is low and the efficacy of chemotherapy agents such as doxorubicin, cisplatin, and 5-fluorouracil is limited [3]. Huachansu injection, derived from a water-soluble extract of the traditional Chinese medicine ChanSu, is commonly used in China to treat patients with hepatocellular carcinoma [4, 5]. ChanSu is obtained from skin and parotid venom secretion glands of toads [6]. Cardiac steroids such as bufalin (BF) are the active components of ChanSu [7]. In the last 20 years, interest of developing cardiac steroids into anticancer agents substantially increased [8,9,10,11,12]. Our lab tried to develop derivatives of BF as possible new anticancer agents [13].
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