Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling

Li, Sha; Shi, Jiazhong; Wang, Liwei; Huang, Yaqin; Zhao, Baixiong; Ding, Hua; Liu, Yuting; Wang, Wuxing; Chen, Zhiwen; Yang, Jin

doi:10.1016/j.freeradbiomed.2022.06.247

Cited by 26 publications

(15 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, inhibition of the PI3K-Akt-mTOR pathway has been previously implicated in this form of cell death [58]. Furthermore, Fak signaling downstream of the glutamate/cystine antiporter SLC7A11 or X c - , which can be inhibited by Riluzole, has also been implicated in ferroptosis [59]. To explore the possibility of ferroptotic cell death, we performed a viability assay after treating Sum44 and LCCTam cells with Vehicle (DMSO), or Riluzole or a combination of Riluzole and Ferrostatin-1 (inhibitor of Ferroptosis).…”

Section: Resultsmentioning

confidence: 99%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsIn the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone.ConclusionsThese findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Besides, their potential use as cancer biomarkers and prognostic factors as well as novel therapeutic targets for cancer therapy has been discussed (for review see [71,72]. EMP1 is a transmembrane glycoprotein involved in oncogenic processes like proliferation, migration, invasion, metastasis, and malignant progression [73][74][75]. In a previous study by our group, we demonstrated that EMP1 knockdown in RB cells signifcantly reduces cell viability and proliferation and increases apoptosis [76].…”

Section: Discussionmentioning

confidence: 99%

Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma

Miroschnikov

Dräger

Meenen

et al. 2023

Journal of Oncology

View full text Add to dashboard Cite

The chemotherapy of retinoblastoma (RB), a malignant ocular childhood disease, is often limited by the development of resistance against commonly used drugs. We identified inositol polyphosphate 4-phosphatase type II (INPP4B) as a differentially regulated gene in etoposide-resistant RB cell lines, potentially involved in the development of RB resistances. INPP4B is controversially discussed as a tumor suppressor and an oncogenic driver in various cancers, but its role in retinoblastoma in general and chemoresistant RB in particular is yet unknown. In the study presented, we investigated the expression of INPP4B in RB cell lines and patients and analyzed the effect of INPP4B overexpression on etoposide resistant RB cell growth in vitro and in vivo. INPP4B mRNA levels were significantly downregulated in RB cells lines compared to the healthy human retina, with even lower expression levels in etoposide-resistant compared to the sensitive cell lines. Besides, a significant increase in INPP4B expression was observed in chemotherapy-treated RB tumor patient samples compared to untreated tumors. INPP4B overexpression in etoposide-resistant RB cells resulted in a significant reduction in cell viability with reduced growth, proliferation, anchorage-independent growth, and in ovo tumor formation. Caspase-3/7-mediated apoptosis was concomitantly increased, suggesting a tumor suppressive role of INPP4B in chemoresistant RB cells. No changes in AKT signaling were discernible, but p-SGK3 levels increased following INPP4B overexpression, indicating a potential regulation of SGK3 signaling in etoposide-resistant RB cells. RNAseq analysis of INPP4B overexpressing, etoposide-resistant RB cell lines revealed differentially regulated genes involved in cancer progression, mirroring observed in vitro and in vivo effects of INPP4B overexpression and strengthening INPP4B’s importance for cell growth control and tumorigenicity.

show abstract

“…It has been reported that the ferroptosis‐related genes, ferroptosis suppressor protein 1 (FSP1) and CDGSH iron sulfur domain 1 (CISD1), are highly expressed in gastric cancer tissues and are associated with poor overall survival of patients (Zang et al, 2023). Furthermore, epithelial membrane protein 1 (EMP1) deficiency promoted the expression of solute carrier family 7 member 11 (SLC7A11) by activating the peroxisome proliferator‐activated receptor‐γ (PPARG) signaling pathway, which enhanced cancer metastasis via inhibiting ferroptosis in bladder cancer cells (S. Liu, Shi, et al, 2022). Strikingly, resistance to ferroptosis reduced the sensitivity of ovarian cancer cells to platinum (Q. Zhang, Li, et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis: Potential opportunities for natural products in cancer therapy

Nie,

Shen,

Zhou

et al. 2023

Phytotherapy Research

View full text Add to dashboard Cite

Cancer cells often exhibit defects in the execution of cell death, resulting in poor clinical outcomes for patients with many cancer types. Ferroptosis is a newly discovered form of programmed cell death characterized by intracellular iron overload and lipid peroxidation in the cell membrane. Increasing evidence suggests that ferroptosis is closely associated with a wide variety of physiological and pathological processes, particularly in cancer. Notably, various bioactive natural products have been shown to induce the initiation and execution of ferroptosis in cancer cells, thereby exerting anticancer effects. In this review, we summarize the core regulatory mechanisms of ferroptosis and the multifaceted roles of ferroptosis in cancer. Importantly, we focus on natural products that regulate ferroptosis in cancer cells, such as terpenoids, polyphenols, alkaloids, steroids, quinones, and polysaccharides. The clinical efficacy, adverse effects, and drug–drug interactions of these natural products need to be evaluated in further high‐quality studies to accelerate their application in cancer treatment.

show abstract

Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling

Cited by 26 publications

References 60 publications

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma

Ferroptosis: Potential opportunities for natural products in cancer therapy

Contact Info

Product

Resources

About