Tryptophan metabolism is an essential regulator of tumor immune evasion. However, the effect of tryptophan metabolism on cancer cells remains largely unknown. Here, we find that tumor cells have distinct responses to tryptophan deficiency in terms of cell growth, no matter hepatocellular carcinoma (HCC) cells, lung cancer cells, or breast cancer cells. Further study shows that ERRFI1 is upregulated in sensitive HCC cells, but not in resistant HCC cells, in response to tryptophan deficiency, and ERRFI1 expression level positively correlates with HCC patient overall survival. ERRFI1 knockdown recovers tryptophan deficiency-suppressed cell growth of sensitive HCC cells. In contrast, ERRFI1 overexpression sensitizes resistant HCC cells to tryptophan deficiency. Moreover, ERRFI1 induces apoptosis by binding PDCD2 in HCC cells, PDCD2 knockdown decreases the ERRFI1-induced apoptosis in HCC cells. Thus, we conclude that ERRFI1-induced apoptosis increases the sensitivity of HCC cells to tryptophan deficiency and ERRFI1 interacts with PDCD2 to induce apoptosis in HCC cells.

Background: There have been reports of increased glutamate pyruvate transaminase 2 (GPT2) expression in certain cancers including breast cancer. Although the role of GPT2 as a metabolic enzyme is well understood in breast cancer progression, little is known about the other roles of GPT2, especially exosomal GPT2. Methods: BT549 and BT474 Cells were cultured and their exosomes were isolated by using ultracentrifugation. Cells migrated through the membrane were stained with crystal violet, and then were observed by microscope. Total RNA was extracted from culture cells and transcribed into cDNA, quantitative real-time RT-PCR was used to detect mRNA expression of ICAM1, VCAM1, and MMP9 using SYBR Green qPCR Mix with a 7500 Fast Real-time PCR system. Western blot was used to detect the gene expression of p-lkBa and TSG101 and GPT2 in breast cancer cells. Immunohistochemistry was used to detect the protein expression of GPT2 and BTRC in cancer cells, animal models loaded with metastasis breast cancer cells were established via tail vein injections. Interaction between GPT2 and BTRC in breast cancer cells was investigated via Co-immunoprecipitation. Results: GPT2 was up-regulated in TNBC. Exosomes were isolated effectively from TNBC cells, and confirmed that GPT2 was overexpressed inexosomes. QRT-PCR showed that mRNA expression levels of ICAM1, VCAM1, and MMP9 in TNBC were high. Exosomal GPT2 derived from TNBC enhanced migration and invasion of breast cancer via in vitro cell experiment and in vivo animal model experiment. Exosomal GPT2 binds with BTRC to degrade p-lkBa, and improved metastasis of breast cancer cells. Conclusion: We demonstrated that GPT2 was upregulated in TNBC as well as in exosomes derived from triple-negative breast cancer (TNBC) cells. GPT2 expression was associated with the malignancy of breast cancer and promoted metastasis of breast cancer cells. Moreover, exosomal GPT2 derived from TNBC cells was verified to increase the capacity of breast cancer cells to metastasize through activating betatransducin repeat containing E3 ubiquitin protein ligase (BTRC). This suggested that exosomal GPT2 may be useful for breast cancer patients as a potential biomarker and treatment target.