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YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in non-small cell lung cancer cells.

ABSTRACT: Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and the identification of the apoptotic process of NSCLC is vital for its treatment. Usually, both the expression level and the cell surface level of TNFRSF10B (TNF Receptor superfamily member 10B) will increase after treatment with some chemotherapeutic agents, which plays a critical role in the apoptosis induction. However, the exact molecular mechanism underlying TNFRSF10B regulation remains largely elusive. Here, we found that TNFRSF10B, along with a vesicular trafficking regulator protein, YIPF2, were upregulated after treatment with pemetrexed (PEM) in NSCLC cells. Besides, YIPF2 increased the surface level of TNFRF10B, while YIPF2 knockdown inhibited the upregulation of TNFRSF10B and its recycling to plasma membrane. In addition, RAB8 decreased the cell surface TNFRSF10B by promoting its removing from plasma membrane to cytoplasm. Furthermore, we found that YIPF2, RAB8 and TNFRSF10B proteins interacted physically with each other. YIPF2 could further inhibit the physical interaction between TNFRSF10B and RAB8, thereby suppressing the removing of TNFRSF10B from plasma membrane to cytoplasm mediated by RAB8 and maintaining its high level on cell surface. Finally, using bioinformatics database, the YIPF2-TNFRSF10B axis was confirmed to be associated with the malignant progression of lung cancer. Taken together, we show that YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in NSCLC cells. These findings may be beneficial for the development of potential prognostic markers of NSCLC and may provide effective treatment strategy.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7165181 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in non-small cell lung cancer cells.

Wang Yingying Y Guo Sen S Li Dongmei D Tang Yongkang Y Li Lei L Su Ling L Liu Xiangguo X

Cell death & disease 20200417 4

Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and the identification of the apoptotic process of NSCLC is vital for its treatment. Usually, both the expression level and the cell surface level of TNFRSF10B (TNF Receptor superfamily member 10B) will increase after treatment with some chemotherapeutic agents, which plays a critical role in the apoptosis induction. However, the exact molecular mechanism underlying TNFRSF10B regulation remains largely elusiv ...[more]

PMID: 32303681

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Project description:BACKGROUND: Parthenolide (PTL) is a sesquiterpene lactone which can induce apoptosis in cancer cells and eradicate cancer stem cells such as leukemia stem cells, prostate tumor-initiating cells and so on. However, the mechanism remains largely unclear. METHODS: Lung cancer cells were treated with parthenolide and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the cell survival was assayed by SRB and MTT assay. Cell cycle was evaluated by DNA flow cytometry analysis. TNFRSF10B, PMAIP1, ATF4 and DDIT3 genes were knocked down by siRNA technique. Apoptosis was evaluated by using Annexin V-FITC/PI staining and flow cytometry analysis. RESULTS: Parthenolide (PTL) induces apoptosis and cell cycle arrest in human lung cancer cells. Moreover, PTL treatment in NSCLC cells increases expression of TNFRSF10B/DR5 and PMAIP1/NOXA. Silencing of TNFRSF10B or PMAIP1 or overexpression of CFLAR /c-FLIP (long form) could protect cells from PTL-induced apoptosis. Furthermore, PTL could increase the levels of endoplasmic reticulum stress hallmarks such as ERN1, HSPA5, p-EIF2A, ATF4 and DDIT3. Knockdown of ATF4 and DDIT3 abrogated PTL-induced apoptosis, which suggested that PTL induced apoptosis in NSCLC cells through activation of endoplasmic reticulum stress pathway. More importantly, we found that ATF4, DDIT3, TNFRSF10B and PMAIP1 were up-regulated more intensively, while CFLAR and MCL1 were down-regulated more dramatically by PTL in A549/shCDH1 cells than that in control cells, suggesting that PTL preferred to kill cancer stem cell-like cells by activating more intensive ER stress response in cancer stem cell-like cells. CONCLUSION: We showed that parthenolide not only triggered extrinsic apoptosis by up-regulating TNFRSF10B and down-regulating CFLAR, but also induced intrinsic apoptosis through increasing the expression of PMAIP1 and decreasing the level of MCL1 in NSCLC cells. In addition, parthenolide triggered stronger ER stress response in cancer stem cell-like cells which leads to its preference in apoptotic induction. In summary, PTL induces apoptosis in NSCLC cells by activating endoplasmic reticulum stress response.

Project description:β-Lactam antibiotics exploit the essentiality of the bacterial cell envelope by perturbing the peptidoglycan layer, typically resulting in rapid lysis and death. Many Gram-negative bacteria do not lyse but instead exhibit "tolerance," the ability to sustain viability in the presence of bactericidal antibiotics for extended periods. Antibiotic tolerance has been implicated in treatment failure and is a stepping-stone in the acquisition of true resistance, and the molecular factors that promote intrinsic tolerance are not well understood. Acinetobacter baumannii is a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. Carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treat A. baumannii infections, but treatment failure is increasingly prevalent. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptible A. baumannii clinical isolates demonstrate tolerance to high-level meropenem treatment, form spheroplasts upon exposure to the antibiotic, and revert to normal growth after antibiotic removal. Using transcriptomics and genetic screens, we show that several genes associated with outer membrane integrity maintenance and efflux promote tolerance, likely by limiting entry into the periplasm. Genes associated with peptidoglycan homeostasis in the periplasm and cytoplasm also answered our screen, and their disruption compromised cell envelope barrier function. Finally, we defined the enzymatic activity of the tolerance determinants penicillin-binding protein 7 (PBP7) and ElsL (a cytoplasmic ld-carboxypeptidase). These data show that outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to A. baumannii meropenem tolerance. IMPORTANCE Carbapenem treatment failure associated with "superbug" infections has rapidly increased in prevalence, highlighting the urgent need to develop new therapeutic strategies. Antibiotic tolerance can directly lead to treatment failure but has also been shown to promote the acquisition of true resistance within a population. While some studies have addressed mechanisms that promote tolerance, factors that underlie Gram-negative bacterial survival during carbapenem treatment are not well understood. Here, we characterized the role of peptidoglycan recycling in outer membrane integrity maintenance and meropenem tolerance in A. baumannii. These studies suggest that the pathogen limits antibiotic concentrations in the periplasm and highlight physiological processes that could be targeted to improve antimicrobial treatment.

Dataset Information

YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in non-small cell lung cancer cells.

Publications

YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in non-small cell lung cancer cells.

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