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Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential.

ABSTRACT: The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities.

SUBMITTER: Khan S

PROVIDER: S-EPMC2669990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model.

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A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy.

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JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix.

Project description:BACKGROUND:Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. METHODS:Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. RESULTS:Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. CONCLUSIONS:The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.

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Cucurbitacin E Exerts Anti-Proliferative Activity via Promoting p62-Dependent Apoptosis in Human Non-Small-Cell Lung Cancer A549 Cells.

Project description:EGFR tyrosine kinase inhibitors (TKIs) are the first-line treatment for advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR and KRAS mutation are ineligible for EGFR-TKIs. Therefore, the discovery of new therapeutic agents is urgently needed for NSCLC patients who cannot receive targeted therapies. Natural products possess tremendous chemical diversity and have been extensively investigated for their anticancer activity. In this study, we found that Cucurbitacin E (Cu E), a triterpene of cucurbitacins widely presented in the edible plants of the Cucurbitaceae family, significantly inhibits the viability and proliferation of A549 cells that harbor wild-type EGFR and KRAS mutation. Our results revealed that Cu E increases cell-cycle arrest at G2/M and subG1 phase. Mechanistically, Cu E significantly inhibits the phosphorylation and protein levels of regulatory proteins and hinders G2/M cell-cycle progression. Meanwhile, the treatment of Cu E resulted in DNA damage response and apoptosis. For the first time, we observed that Cu E induces incomplete autophagy as evidenced by increased LC3B-II expression and p62-accumulation. Knockdown of p62 rescued the cells from Cu E-mediated anti-proliferative effect, apoptosis, DNA damage, and ROS production. These findings suggest that Cu E is a promising drug candidate for NSCLC.

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Cell-permeable bone morphogenetic protein 2 facilitates bone regeneration by promoting osteogenesis.

Project description:The use of the FDA-approved osteoinductive growth factor BMP2 is widespread for bone regeneration. However, its clinical application has been hindered by limitations in cell permeability and a short half-life in circulation. To address this issue, we have developed a modified version of BMP2, referred to as Cell Permeable (CP)-BMP2, which possesses improved cell permeability. CP-BMP2 incorporates an advanced macromolecular transduction domain (aMTD) to facilitate transfer across the plasma membrane, a solubilization domain, and recombinant human BMP2. Compared to traditional rhBMP2, CP-BMP2 exhibits enhanced cell permeability, solubility, and bioavailability, and activates Smad phosphorylation through binding to BMP receptor 2. The effectiveness of CP-BMP2 was evaluated in three animal studies focusing on bone regeneration. In the initial study, mice and rabbits with critical-size calvarial defects received subcutaneous (SC) injections of CP-BMP2 and rhBMP2 (7.5 mg/kg, 3 injections per week for 8 weeks).Following 8 weeks of administration, CP-BMP2 demonstrated a remarkable 65 % increase in bone formation in mice when compared to both the vehicle and rhBMP2. Moreover, rabbits exhibited faster bone formation, characterized by a filling pattern originating from the center. In a subsequent study involving injured horses, hind limb bones treated with CP-BMP2 exhibited an 85 % higher bone regeneration rate, as evidenced by Micro-CT results, in contrast to horses treated with the vehicle or rhBMP2 (administered at 150 μg/defect, subcutaneously, once a week for 8 weeks, without a scaffold). These results underscore the potential of CP-BMP2 to facilitate rapid and effective healing. No noticeable adverse effects, such as ectopic bone formation, were observed in any of the studies. Overall, our findings demonstrate that CP-BMP2 holds therapeutic potential as a novel and effective osteogenic agent.

| S-EPMC10848039 | biostudies-literature

Blocking COX-2 induces apoptosis and inhibits cell proliferation via the Akt/survivin- and Akt/ID3 pathway in low-grade-glioma.

Project description:Approximately half of surgically-treated patients with low-grade-glioma (LGG) suffer recurrence or metastasis. Currently there is no effective drug treatment. While the selective COX-2 inhibitor celecoxib showed anti-neoplastic activity against several malignant tumors, its effects against LGG remain to be elucidated. Ours is the first report that the expression level of COX-2 in brain tissue samples from patients with LGG and in LGG cell lines is higher than in the non-neoplastic region and in normal brain cells. We found that celecoxib attenuated LGG cell proliferation in a dose-dependent manner. It inhibited the generation of prostaglandin E2 and induced apoptosis and cell-cycle arrest. We also show that celecoxib hampered the activation of the Akt/survivin- and the Akt/ID3 pathway in LGGs. These findings suggest that celecoxib may have a promising therapeutic potential and that the early treatment of LGG patients with the drug may be beneficial.

| S-EPMC6763415 | biostudies-literature

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Project description:Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development, but little is known about their involvement in the early steps of tumorigenesis. To identify lncRNAs dysregulated in precancerous lesions, we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the nontumorous gastric mucosa of patients with gastric cancer (GC) and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 is specifically upregulated in GC patients and that expression of TM4SF1-AS1 is prevalently elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell proliferation in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interaction with Pur-α and YB-1. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1‑AS1 associates with several stress granule (SG)-related proteins, including G3BP2, RACK1 and DDX3. Notably, TM4SF1-AS1 promotes SG formation and inhibits apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1‑AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggest TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

2023-09-16 | PXD036766 | JPOST Repository

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