MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer

Abstract

Background 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). Methods Co-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. Results We 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. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

“…Although emerging evidence has improved our understanding of TRIM72 function and its diagnostic and prognostic value in human cancers, the mechanisms involving TRIM72 and cancer development remain poorly understood. Recent studies have unraveled that reduced TRIM72 expression is implicated in a variety of cancer types and cancer-related processes, including proliferation, invasion, and prognosis [ 25 – 28 ]. Here, we demonstrated that TRIM72 expression was reduced in BC tissues and cell lines; and overexpression of TRIM72 suppressed tumor progression both in vitro and in vivo .…”

“…A deteriorating TME accompanies the increased expression of transcription factors to regulate metabolism, proliferation, and inflammation [ 36 ]. Recently, treatment with the recombinant human MG53 (TRIM72) could inhibit lung cancer tumor growth by blocking ATO-induced SG formation, suggesting that TRIM72 is a key mediator of cancer cells exposed to adverse environments [ 28 ]. Despite the stress-related repressor of TRIM72 having been implicated by previous studies [ 23 , 24 ], the role of TRIM72 in TME-induced pressure and the molecular mechanisms is not well known.…”

“…Researchers also found that TRIM72 knockdown in SCC25 cells could promote the phosphorylation of Akt Ser208 and Akt Thr473 , which contribute to tumorigenicity changes in tongue cancer [ 27 ]. In non-small cell lung cancer cells, loss of TRIM72 was found to promote lung tumorigenesis by interacting with an oncogenic protein G3BP2 to regulate stress granule (SG) formation under arsenic trioxide (ATO)-induced oxidative stress conditions [ 28 ]. As such, TRIM72 could be an effective treatment target to protect against a range of adverse stresses.…”

Single-Cell RNA Sequencing Unravels Distinct Tumor Microenvironment of Different Components of Lung Adenocarcinoma Featured as Mixed Ground-Glass Opacity

“…Stress granules are mRNPs stalled in translation initiation ( 72 ). Targeting these structures has been proven to be a feasible therapy for NSCLC based on a recent study ( 73 ). Our finding suggests that it might be effective to target pre-invasive lesions when it is still characterized by GGO.…”

CNST is Characteristic of Leukemia Stem Cells and is Associated With Poor Prognosis in AML

“…SGs are involved in posttranscriptional regulation and translational control. SGs have been found in a variety of tumors and are thought to improve the tolerance of tumor cells to stress stimuli and chemotherapeutic agents ( Grabocka and Bar-Sagi, 2016 ; Li et al, 2021 ). SGs may be related to the formation of the P-body because a certain proportion of RNA-binding proteins (RBPs) and mRNAs shared by SGs and PBs have been found to shuttle between the two when the SG assembly is induced ( Kedersha et al, 2005 ; Moon et al, 2019 ).…”