The effects of mitochondrial dysfunction on the cell cycle

Hyperproliferative disorders, such as pulmonary arterial hypertension (PAH) and cancers, are characterized by excessive cell proliferation and resistance to apoptosis (Dasgupta et al., 2021). This “neoplastic phenotype” is due, at least in part, to acquired changes in mitochondrial metabolism. While perturbation of mitochondrial metabolism, notably a shift to aerobic glycolysis (Warburg phenomenon) contributes to the proliferation/apoptosis imbalance in cells from hyperproliferative disease origin, a newly recognized abnormality, namely, dysregulation of mitochondrial dynamics has been identified (Rehman et al., 2012). Mitochondria continuously join together (fusion) and divide (fission) thereby maintaining network quality control (Mao and Klionsky, 2013), mediating cell death (Tian et al., 2017) and regulating metabolism and the cell cycle (Chen et al., 2018). The major mediator of mitochondrial fission is dynamin-related protein 1 (Drp1); while fusion is meditated by mitofusin-1 and mitofusin-2 (Archer, 2013). Upon activation, Drp1 is recruited from the cytosol to the mitochondrial outer membrane (OMM) via interaction with its receptor proteins in a poorly understood multimerization reaction. In mammals, there are four proteins on the mitochondrial outer membrane that act as Drp1 receptors: mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively) (Atkins et al., 2016). Mitotic fission coordinates mitochondrial and nuclear division, ensuring equitable distribution of mitochondria between daughter cells. Mitotic fission occurs via a Drp1-dependent process. Several studies have shown that inhibition of mitotic fission triggers a cell cycle checkpoint and results in cell cycle arrest and apoptosis (Chen et al., 2018) both in cancers and in non-malignant, hyperproliferative diseases such as PAH (Marsboom et al., 2012). Thus, mitotic fission is an appealing therapeutic target. It has also been shown that Drp1 expression is upregulated in hyperproliferative diseases and Drp1 is postranslationally activated (Marsboom et al., 2012; Rehman et al., 2012; Tian et al., 2018; Abu-Hanna et al., 2023). Inhibition of Drp1 regresses cancer and PAH in animal models (Marsboom et al., 2012; Rehman et al., 2012). In this special edition of Frontiers in Cell and Developmental Biology, four journal articles on The effects of mitochondrial dysfunction on the cell cycle were published: Two original research articles, one review, and one mini-review. Three articles are relevant to pulmonary hypertension (PH), and the other is related to diabetes

A retrospective analysis of ezrin protein and mRNA expression in breast cancer: Ezrin expression is associated with patient survival and survival of patients with receptor‐positive disease

Introduction: The cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early‐stage breast cancer patients using the Nottingham (n = 1094) and METABRIC (n = 1980) cohorts, respectively. Results: High expression of ezrin was significantly associated with larger tumour size (p = 0.027), higher tumour grade (p < 0.001), worse Nottingham Prognostic Index prognostic group (p = 0.011) and HER2‐positive status (p = 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p < 0.001) and remained associated with survival in multivariate Cox‐regression analysis (p = 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051–1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p < 0.001) in comparison to those categorised as triple‐negative breast cancer (p = 0.889). High expression of ezrin mRNA (VIL2) in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p < 0.001). Conclusion: Retrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor‐positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early‐stage breast cancer

Effect of 18F-fluciclovine positron emission tomography on the management of patients with recurrence of prostate cancer: Results from the FALCON Trial

Purpose: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. Methods and Materials: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. Results: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA &gt;2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). Conclusions: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy

A novel role for ezrin in breast cancer angio/lymphangiogenesis

Abstract Introduction Recent evidence suggests that tumour lymphangiogenesis promotes lymph node metastasis, a major prognostic factor for survival of breast cancer patients. However, signaling mechanisms involved in tumour-induced lymphangiogenesis remain poorly understood. The expression of ezrin, a membrane cytoskeletal crosslinker and Src substrate, correlates with poor outcome in a diversity of cancers including breast. Furthermore, ezrin is essential in experimental invasion and metastasis models of breast cancer. Ezrin acts cooperatively with Src in the regulation of the Src-induced malignant phenotype and metastasis. However, it remains unclear if ezrin plays a role in Src-induced tumour angio/lymphangiogenesis. Methods The effects of ezrin knockdown and mutation on angio/lymphangiogenic potential of human MDA-MB-231 and mouse AC2M2 mammary carcinoma cell lines were examined in the presence of constitutively active or wild-type (WT) Src. In vitro assays using primary human lymphatic endothelial cells (hLEC), an ex vivo aortic ring assay, and in vivo tumour engraftment were utilized to assess angio/lymphangiogenic activity of cancer cells. Results Ezrin-deficient cells expressing activated Src displayed significant reduction in endothelial cell branching in the aortic ring assay in addition to reduced hLEC migration, tube formation, and permeability compared to the controls. Intravital imaging and microvessel density (MVD) analysis of tumour xenografts revealed significant reductions in tumour-induced angio/lymphangiogenesis in ezrin-deficient cells when compared to the WT or activated Src-expressing cells. Moreover, syngeneic tumours derived from ezrin-deficient or Y477F ezrin-expressing (non-phosphorylatable by Src) AC2M2 cells further confirmed the xenograft results. Immunoblotting analysis provided a link between ezrin expression and a key angio/lymphangiogenesis signaling pathway by revealing that ezrin regulates Stat3 activation, VEGF-A/-C and IL-6 expression in breast cancer cell lines. Furthermore, high expression of ezrin in human breast tumours significantly correlated with elevated Src expression and the presence of lymphovascular invasion. Conclusions The results describe a novel function for ezrin in the regulation of tumour-induced angio/lymphangiogenesis promoted by Src in breast cancer. The combination of Src/ezrin might prove to be a beneficial prognostic/predictive biomarker for early-stage metastatic breast cancer