Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Modifications in dietary intake and adherence to the Mediterranean diet can importantly increase life expectancy, reduce the risk of developing cancer or chronic diseases and improve the quality of life. Indeed, the study of the antitumor properties of food components is gaining more and more attention. Recently, many studies have demonstrated antiproliferative and antiangiogenic activities of natural aliments such as mangosteen, grape, tomato or chestnut extracts in cancer. Among natural aliments, Olea europaea leaves, oil and fruits have been shown to inhibit proliferation and induce apoptosis in several cancer cells. Among these compounds, polyphenols have been reported to interfere with the initiation, promotion and progression of cancer by affecting tumorigenic cell transformation. Nevertheless, Olive leaves still remain a non‐edible source rich in polyphenols that can play an interesting role in cancer. Breast and ovarian cancers are two of the most frequently diagnosed tumors, and the main and fifth reason of tumor death among females, respectively. In this study, for the first time we investigated the antitumor potential of an Olive Leaf Extract ‐OLE‐ rich in polyphenols (>70% of its content) in MDA‐MB‐231 triple negative breast and OVCAR‐3 ovarian cancer cells. Our results indicate that OLE selectively inhibits MDA‐MB‐231 and OVCAR‐3 cell viability inducing an arrest in S‐phase in MDA‐MB‐231 and in G2/S‐phase in OVCAR‐3 cells, following treatment with OLE at 250 μg/mL and 200 μg/mL in MDA‐MB‐231 and OVCAR‐3 cells respectively for 24h, confirmed by Cyclins B2 and D1 downregulation. We demonstrate that OLE markedly increases apoptotic cell death, investigated by IncuCyte live‐cell Imaging System. Additionally, OLE treatment significantly up regulates the protein levels of cleaved PARP and caspase‐9 in MDA‐MB‐231 and OVCAR‐3 cells. A significant decrease of the mitochondrial mass in terms of MitoTracker Red staining in both cancer cells, together with a reduction of mitochondrial membrane potential, were observed after OLE treatment, using IncuCyte live‐cell Imaging System and fluorescence experiments. Furthermore, OLE treatment resulted in an increased level of intracellular reactive oxygen species (ROS) and mitochondrial superoxide, together with a decreased activity of enzymes such as catalase (CAT) and superoxide dismutase (SOD2), confirming oxidative stress in both MDA‐MB‐231 and OVCAR‐3 cells. These are the first data to demonstrate that OLE exerts a proapoptotic activity on human breast and ovarian cancer cells through ROS generation and mitochondrial impairment, in agreement with recent findings indicating a pro‐oxidant activity of polyphenols in cancer. Therefore, in order to obtain a better quality of life and an increased longevity, OLE might represent an attractive candidate for tumor prevention and drug development against breast and ovarian cancers. Support or Funding Information This project has received funding from the European Union’s Horizon 2020 research and innovation programme under th...