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Rapamycin suppresses small bowel adenocarcinoma HUTU 80 cells proliferation by inhibiting hypoxia-inducible factor-1α
Bao-Peng Pu1, Peng-Hui Wang1,2, Kai-Kai Guo1,3
1Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou 571199, Hainan Province, China.
Background:
Small bowel adenocarcinoma (SBA) is a rare malignant tumor of gastrointestinal tract. Currently, there is no standard treatment approach for late-stage SBA, which lead to poor outcome and prognosis. Rapamycin is an immunosuppressive agent that has been reported to inhibit the proliferation of tumor cells. However, whether rapamycin inhibit the growth of SBA remains to be investigated.
Aim:
To observe the inhibitory effect of rapamycin on small intestinal adenocarcinoma cells.
Methods:
Methylthiazolyldiphenyl-tetrazolium bromide assay, colony formation assay, cell cycle analysis, and glycolysis assay were used to observe the phenotypic changes of rapamycin-treated HUTU 80 cells. RNA sequencing and untargeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) metabolomics were also used to find the potential targets of action of rapamycin in inhibiting HUTU 80 cells proliferation, and validate potential targets by quantitative polymerase chain reaction and western blotting. The construction of a subcutaneous HUTU 80 xenograft in BALB/c nude mice was used to explore the tumor suppression effect of rapamycin.
Results:
Rapamycin inhibited HUTU 80 cell proliferation in vitro and in vivo. Rapamycin inhibited the migration, invasion, and glycolysis of HUTU 80 cells, and induced cell cycle arrest. RNA sequencing and untargeted UHPLC-MS/MS metabolomic analysis indicated that the mechanism of rapamycin action was linked to the hypoxia-inducible factor (HIF)-1α signaling pathway and the related gluconeogenesis/glycolysis pathways. Subsequent experiments found that rapamycin downregulated the messenger RNA expression of HIF-1α and its downstream target genes, LDHA, PDK1 and VEGF. Additionally, rapamycin inhibited expression of phosphorylated mammalian target of rapamycin (mTOR), phosphorylated-70 kDa ribosomal protein S6 kinase (p70S6k), phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and HIF-1α proteins in vitro and in vivo.
Conclusion:
Downregulation of mTOR/p70S6k/4E-BP1/HIF-1α signaling pathway activation, leading to decreased glycolysis and cell cycle arrest, may be the pivotal mechanism by which rapamycin inhibits SBA.
Insights
Rapamycin effectively inhibits small bowel adenocarcinoma (SBA) cell growth by downregulating the mTOR/p70S6k/4E-BP1/HIF-1α pathway, reducing glycolysis, and arresting the cell cycle.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Small bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy with limited late-stage treatment options.
- Rapamycin, an immunosuppressive drug, shows potential in inhibiting tumor cell proliferation.
- The efficacy of rapamycin against SBA remains largely uninvestigated.
Purpose of the Study:
- To investigate the inhibitory effects of rapamycin on small intestinal adenocarcinoma (SIA) cells.
- To elucidate the underlying molecular mechanisms of rapamycin's action in SIA.
Main Methods:
- In vitro assays (MTT, colony formation, cell cycle, glycolysis) were performed on HUTU 80 cells treated with rapamycin.
- RNA sequencing and UHPLC-MS/MS metabolomics identified potential targets.
- In vivo studies utilized a HUTU 80 xenograft model in nude mice.
Main Results:
- Rapamycin significantly inhibited HUTU 80 cell proliferation, migration, invasion, and glycolysis in vitro and in vivo.
- Rapamycin induced cell cycle arrest in HUTU 80 cells.
- Mechanism involves downregulation of the mTOR/p70S6k/4E-BP1/HIF-1α signaling pathway, impacting glycolysis and gluconeogenesis.
Conclusions:
- Rapamycin demonstrates potent anti-cancer effects against small bowel adenocarcinoma.
- The mTOR/p70S6k/4E-BP1/HIF-1α pathway is a key target for rapamycin in SBA treatment.
- Rapamycin's inhibition of glycolysis and induction of cell cycle arrest are critical to its anti-SBA activity.
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