Linking phosphoinositide function to mitosis.

Phosphoinositides (PtdIns) are a family of differentially phosphorylated lipid second messengers localized to the cytoplasmic leaflet of both plasma and intracellular membranes. Kinases and phosphatases can selectively modify the PtdIns composition of different cellular compartments, leading to the recruitment of specific binding proteins, which control cellular homeostasis and proliferation. Thus, while PtdIns affect cell growth and survival during interphase, they are also emerging as key drivers in multiple temporally defined membrane remodeling events of mitosis, like cell rounding, spindle orientation, cytokinesis, and abscission.

A connection between phosphatidylinositol 5-phosphate and the Hippo pathway to prevent epithelial-mesenchymal transition in cancer.

The Hippo pathway blocks epithelial-mesenchymal transition and metastasis in cancer mediated by the transcriptional coactivator YAP. In this issue of , Palamiuc demonstrate that phosphatidylinositol 5-phosphate (PI5P) enhances Hippo pathway activation and that simultaneously the Hippo pathway initiates a positive feedback loop by inhibiting the conversion of PI5P into PIP.

Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma.

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses and disease progression remain common. Therefore, a major challenge is the development of novel therapeutic approaches to overcome drug resistance, improve patient outcomes, and broaden PIs applicability to other pathologies.

Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer.

Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype.

PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation.

Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P–binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36).

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer.

Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade.

Preventing and Treating Anthracycline Cardiotoxicity: New Insights.

Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood.