Abstract
BackgroundCancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC).MethodsCo-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis.ResultsWe show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model.ConclusionOverall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.
Highlights
Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein Ras GTPase-activating proteinbinding protein 2 (G3BP2)
We found that the Tripartite Motif (TRIM)-motif of Mitsugumin 53 (MG53) can interact with G3BP2 to regulate SG formation in non-small cell lung cancer (NSCLC) cells under stress conditions
To understand the physiologic role of MG53 in regulation of tumor growth, we conducted allograft transplantation of mouse NSCLC cells (Braf V600E/+Atg7−/−) 50 into wild type, mg53-/, and tissue-plasminogen activator (tPA)-MG53 mice [41]. 4x106 cells were injected into the flanks of mice subcutaneously
Summary
Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Lung cancer is a leading cause of mortality worldwide, afflicting approximately 170,000 people each year in the United States, and non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases [1, 2]. In 2020, it is estimated that the United States will have more than 1806,590 new cancer cases, and lung cancer accounted for more cancer-related deaths than breast, prostate, and colon cases combined [2]. There is a great need for novel therapeutic agents to treat NSCLC more effectively. The search for novel tumor-suppressive factors that inhibit tumor progression represents an important area of cancer research
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