Protective effects of hepatic stellate cells against cisplatin-induced apoptosis in human hepatoma G2 cells

Abstract

Abstract. The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously reported. However, the detailed mechanisms responsible for these effects remain unclear. In this study, we investigated the effects of HSCs on cisplatin-induced apoptosis in human hepatoma HepG2 cell lines. HepG2 cells were treated with cisplatin alone or co-cultured with LX-2 cells 3 days before incubation with cisplatin. Cisplatin causes apoptosis in HepG2 cells and LX-2 cells protect HepG2 cells from death. The protection of LX-2 cells against cisplatin-induced cytotoxicity in HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by cytotoxicity assay and nuclear staining analysis. p53 and Bax mRNA levels were elevated, and cell cycle arrest was produced after cisplatin treatment. LX-2 cells suppressed this elevation of p53 and Bax as well as the cell cycle arrest induced by cisplatin, when compared with those of the treated cells with cisplatin alone. The LX-2 cells pretreatment inhibited the cisplatin-induced apoptosis, which was related with the incomplete blockage in p53 activation.In summary, the results of our present study demonstrate that HSCs protect HepG2 cells against cisplatin-induced apoptosis and its protective effects occur via inhibiting the activation of p53, which is of critical importance for enhanced understanding of fundamental cancer biology. IntroductionHepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third most common leading cause of cancer-related death worldwide, and the burden of this devastating cancer is expected to increase in coming years (1,2). The majority of patients are diagnosed at advanced stage and thus not in a position for curative treatments (3), which have very limited options, and the only systemic therapy currently approved is sorafenib, an oral tyrosine kinase inhibitor drug targeting multiple signalling pathways. The objective response rate (ORR), however, was poor (4). Cisplatin is a widely used anticancer agent and has a broad range of antitumor activity, which is likely a result of inhibition of replication by cisplatin-DNA adducts and induction of apoptosis (5). HCC is considered a poor responder to chemotherapy and a standard systemic treatment does not exist for patients for whom sorafenib is unsuitable or unavailable. The reason could be the frequently observed development of multidrug tumor resistance, which is related to the high expression of the multidrug-resistance gene (6-9). The progression of cancer is no longer recognized as an independent event which only relates to the genetic mutation and uncontrollable growth of cancer cells. New therapeutic strategies are urgently needed, and these will most likely result from a better understanding of the cell biology of HCC.The interaction between tumor cells and their microenvironment has been recognized to fundamentally affect tumor progression (10-12). Physiologically, the surrounding microenvironment constitutes an important barrier to cell t...

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“…Western blot analyses were conducted as previously described (31). After every specific treatment, cells were washed with precooled PBS and lysed on ice with 1 mM phenylmethanesulfonyl fluoride and RIPA buffer (Beyotime, cat no.…”

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