Abstract
Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are generated by microbial fermentation of indigestible fiber by gut flora. SCFAs are ligands of two orphan G protein-coupled receptors, GPR41 and GPR43, that modulate cell proliferation and induce apoptosis. However, it is unclear if SCFAs enhance the effects of chemotherapy in a GPR41- or GPR43-dependent manner. The aim of this study was to investigate whether SCFAs, and particularly propionate, activate GPR41 or GPR43, and thereby enhance the antitumor effects of cisplatin in HepG2 human hepatocellular carcinoma (HCC) cells. The inhibitory effects of propionate and cisplatin on proliferation of HCC cells were determined by MTS assay. Changes in apoptosis rate were analyzed by flow cytometry. The effects of combined propionate and cisplatin on these properties in HCC cells were significantly higher than those of cisplatin alone. With combined treatment, the levels of cleaved caspase-3, active caspase-3 forms, and acetylated histone H3 were enhanced in a GPR41-dependent manner; expression of histone deacetylases (HDAC) 3, 4, 5, 6, 8 proteins was significantly reduced; and induction of TNF-α expression was significantly enhanced. These results suggest that propionate and cisplatin synergistically and significantly induce apoptosis of HepG2 cells by increasing expression of autocrine TNF-α via reduction of HDACs through GPR41 signaling. From clinical and translational perspectives, our data suggest that a combination of propionate with cisplatin may have better therapeutic effects on HCC compared with conventional treatment, and that a selective GPR41 agonist may be a candidate as an adjuvant therapeutic agent for HCC.
Highlights
Hepatocellular carcinoma (HCC) is a major malignant cancer worldwide and the third leading cause of cancer death [1]
Immunoblot analyses showed that GPR41 and GPR43 were present as bands of approximately 39 kDa and 43 kDa, respectively, in all hepatocellular carcinoma (HCC) cell lines, including HepG2, HuH-7, JHH-4 and HLE (Figure 1D)
We showed that GPR41 and GPR43 are moderately expressed in human HCC, and we found that a SCFA, propionate, enhanced the chemosensitivity of HepG2 cells to cisplatin by inducing TNF-α expression via GPR41 activation involving Gi/o and Gβ/γ
Summary
Hepatocellular carcinoma (HCC) is a major malignant cancer worldwide and the third leading cause of cancer death [1]. The mortality rate in most countries is almost equal to the incidence of HCC, indicating the lack of effective treatment. Surgical resection is the most common treatment for HCC. The clinical symptoms of HCC are not clear in the early stage, and the disease is often diagnosed at an advanced stage. Patients with inoperable HCC are commonly treated with cisplatin chemotherapy [2], which is effective, but toxic to normal tissue. Development of a drug with low toxicity that is relatively selective for HCC and with a synergistic effect with established chemotherapeutic drugs may prolong survival of patients with HCC, those in an advanced stage
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