CHEMOSENSITIZING EFFECTS OF GDF11 IN HUMAN HEPATOCELLULAR CARCINOMA CELLS

Abstract

Introduction and Objectives: Hepatocellular carcinoma (HCC) ranks as the second leading cause of cancer death globally; this neoplasm accounts for approximately 90% of liver cancers, and about 850,000 new cases are reported annually. Several factors increase the likelihood of developing HCC, such as excessive alcohol consumption, hepatitis B and C virus infection, metabolic syndrome, and a diet high in lipids and cholesterol. The chronic lesions that the liver can suffer due to the aggression of these factors usually generate lower grade pathologies such as fatty liver, hepatitis, and cirrhosis, which can evolve into HCC. In 2019 Gerardo-Ramirez and collaborators from our group reported the ability of GDF11 to subtract aggressiveness to several HCC-derived cell lines HCC (Huh7, Hep3B, SNU-182, Hepa 1-6 and HepG2); they found that GDF11 reduced proliferation, metastatic capacity, colony, and spheroid formation and invasiveness in those cell lines. Findings by Gerardo-Ramirez et al. (2019) identified transcriptional repression of cyclins D1 and A and overexpression of p27. Additionally, an increase in the expression of epithelial markers E-cadherin and Occludin was observed; conversely, mesenchymal-type features such as N-cadherin and Snail decreased with GDF11 treatment, confirming that this growth factor-induced a mesenchymal to epithelial transition. Furthermore, our group reported the effect of GDF11 in reducing lipid content, especially cholesterol and triglycerides. It was also confirmed that GDF11 reduced mevalonate pathway proteins in Huh7 and Hep3B liver cancer cell lines. Additionally, they reported that GDF11 was able to impair mitochondrial functionality and its structure. Moreover, GDF11 treatment induced an alteration of glycolytic capacity and oxygen consumption rate in these models. Objectives General: To determine the sensitizing effect of GDF11 in the Hep3B cell line. Specific: To determine the capacity of GDF11 in the reduction of the EC50 of cisplatin. Methods: We used the HCC cell line Hep3B (ATCC). A 72-h pretreatment with GDF11 or without was performed; then we treated the cells with cisplatin at various concentrations (0, 2.5, 5, 10, 15, 15, 25, 50, and 100 μM), incubated for 48 h, and cell viability assay was performed by crystal violet. Results: In our experiments, GDF11 has shown an increased sensitivity of Hep3B cells to cisplatin treatment by significantly reducing the mean effective dose (EC50) from 22.26 μM to 8.11 μM this result was observed by crystal violet assay and by light microscopy. Discussion: Results demonstrate that GDF11 has sensitizing effects against cisplatin treatment on the liver tumor cell line Hep3B. This agrees with previous results of our group where a detrimental impact in liver tumor cells is observed by the GDF11 treatment and contrast with other works where TGF-β family members have chemoresistance effects. Conclusions: GDF11 pretreatment sensitizes the HCC cell line Hep3B by reducing the cisplatin EC50.Conacyt Fronteras de la Ciencia 1320The authors declare that there is no conflict of interest.