Falcarindiol Enhances Cisplatin Chemosensitivity of Hepatocellular Carcinoma via Down-Regulating the STAT3-Modulated PTTG1 Pathway

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy globally and the third leading cause of cancer-related death. Chemotherapy is one of the main methods in treating HCC, while recent studies have found that the resistance of HCC to chemotherapeutic drugs reduces the efficacy of the chemotherapy. Falcarindiol (FAD) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae), while its role in HCC remains to be explored. Here, HCC cells (Huh7 and LM3) were treated with FAD at different doses. Cell proliferation was tested by the cell counting kit-8 (CCK-8) method and colony formation assay, while the apoptosis was monitored by flow cytometry. The profiles of apoptosis-related proteins (Bax, bcl2, and Caspase-3), DNA repair proteins (Rad51, BRCA1, and MDC1), and the signal transducer and activator of transcription 3 (STAT3)/Pituitary Tumor Transforming Gene 1 (PTTG1) were verified by western blot (WB) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The interaction between STAT3 and PTTG1 was verified by immunoprecipitation (IP). In addition, a xenograft tumor model was constructed in mice to explore the anti-tumor effects of FAD in vivo, and immunohistochemistry (IHC) was performed to count the number of Ki67-stained cells. As a result, FAD inhibited HCC cell proliferation and DNA repair, facilitated their apoptosis, and also enhanced cisplatin (DDP) chemosensitivity. The Combination Index (CI) evaluation showed that FAD and DDP had synergistic effects in repressing HCC cell proliferation. Besides, FAD dampened the STAT3/PTTG1 pathway expression. Further studies revealed that inhibiting STAT3 enhanced the inhibitive effect of FAD on HCC cells, whereas overexpressing PTTG1 attenuated the anti-tumor effect of FAD. Overall, our study illustrated that FAD is a potential anticancer drug and strengthens the chemosensitivity of HCC cells to DDP by inhibiting the STAT3/PTTG1 pathway.

ADAM12 is an independent predictor of poor prognosis in liver cancer

“…In addition, the JAK/STAT and MAPK signalling pathways are associated with antitumour immunity 59 . Both the JAK/STAT and MAPK pathways have been confirmed to be crucial targets in related studies of HCC resistance 60 , 61 .…”

Falcarindiol attenuates cisplatin-induced nephrotoxicity through the modulation of NF-kB and Nrf2 signaling pathways in mice

“…FAD led to cell death through the induction of apoptosis, autophagy and endoplasmic reticulum stress. It is important to note that FAD did not interfere with cisplatin e ciency, and interestingly had synergistic effects in combination with cisplatin to suppress HCC cells (Hong et al, 2021). These results emphasize on the anti-cancer potential of FAD in addition to its anti-in ammatory and antioxidant capabilities; Nevertheless, the effects of FAD treatment on normal stem cells have not been fully evaluated yet; for example, one study exhibited deleterious effects for FAD on the neural stem cells in which impairs the balance between self-renewal and differentiation status (Kim et al, 2018).…”

Clinical significance of securin expression in solid cancers: A PRISMA-compliant meta-analysis of published studies and bioinformatics analysis based on TCGA dataset

“…[ 15 ] Moreover, it has also been demonstrated that securin played a critical role in facilitating EMT, invasion, metastasis, and chemoresistance of HCC cells. [ 76 , 77 ] In colorectal cancer, securin can lead to genetic instability by inhibiting Ku70 activity and disturbing the nonhomologous end-joining dsDNA repair pathway. [ 16 ] In addition, accumulated evidence has shown that securin represses drug-induced senescence and apoptosis [ 26 , 63 , 78 , 79 ] and contributes to the migration and invasion of colorectal cancer cells.…”