Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Abstract

Background Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral ( R )-2-hydroxy FAs (( R )-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo . Findings FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with ( R )-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo . Moreover, ( R )-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that ( R )-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund Grants of NSF, NIH, and PAPD.

Tac2‑N serves an oncogenic role and promotes drug resistance in human gastric cancer cells

“…The survival rate of AGS cells varied depending on the expression levels of TC2N; TC2N knockdown significantly decreased the cell survival rate, reflecting a higher sensitivity of AGS cells to DPP, paclitaxel and 5-FU when TC2N expression was inhibited. Acquired drug resistance is one of the predominant reasons for the low cure rate and high recurrence rate in patients with gastric cancer, especially at an advanced stage ( 23 ). Thus, improving the sensitivity of cancer cells to chemotherapeutics may be an important strategy for cancer treatment.…”

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

“…Our results strongly argue that a combination of FA2H and UGT8 expression drives the synthesis of 2-hydroxyHexCer, the exact mechanism accounting for the accumulation of these metabolites specifically in adenocarcinomas, which should be confirmed by ulterior investigations of sulfatides and gangliosides, which were also linked with cancer metastasis (35,36) and multi-drug resistance (37). Aligning with the theory that complex metabolic alterations, rather than single molecule levels, should be taken into account for delineating mechanisms of disease, low FA2H was associated with tumor growth and patient survival in gastric tumors (38), but UGT8 is not overexpressed in gastric tumors in Fig. 2.…”

MicroRNA‑1297 downregulation inhibits breast cancer cell epithelial‑mesenchymal transition and proliferation in a FA2H‑dependent manner

“…FA2H downregulation has been observed in triple negative breast cancer tissues and cell lines (27). FA2H expression levels were lower in gastric tumor tissues compared with healthy control tissues (26). Moreover, another study revealed that FA2H levels were higher in adenocarcinoma compared with squamous and neuroendocrine carcinoma (28).…”

“…As a hydroxy fatty acid enzyme, fatty acid 2-hydroxylase (FA2H) promotes 2-hydroxylation of fatty acid N-acyl chain (23). It has been reported that 2-hydroxyceramide and FA2H, which are expressed in several tissues (24,25), participate in multiple cell signaling pathways, such as the AMPK and mTOR/p70 ribosomal protein S6 kinase 1 (S6K1)/glioma-associated oncogene homolog 1 pathways (26). FA2H also serves a crucial role in the occurrence and development of tumors (26).…”

“…It has been reported that 2-hydroxyceramide and FA2H, which are expressed in several tissues (24,25), participate in multiple cell signaling pathways, such as the AMPK and mTOR/p70 ribosomal protein S6 kinase 1 (S6K1)/glioma-associated oncogene homolog 1 pathways (26). FA2H also serves a crucial role in the occurrence and development of tumors (26). FA2H downregulation has been observed in triple negative breast cancer tissues and cell lines (27).…”