Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD. Treatment of PKD-derived cells with this compound not only reduces PAK4 steady-state protein levels and regulates β-catenin signaling, but also inhibits nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in a key NAD salvage pathway. KPT-9274 can attenuate cellular proliferation and induce apoptosis associated with a decrease in active (phosphorylated) PAK4 and β-catenin in several Pkd1-null murine cell lines, with a less pronounced effect on the corresponding phenotypically normal cells. Additionally, KPT-9274 shows inhibition of cystogenesis in an ex vivo model of cyclic AMP-induced cystogenesis as well as in the early stage Pkd1flox/flox:Pkhd1-Cre mouse model, the latter showing confirmation of specific anti-proliferative, apoptotic, and on-target effects. NAD biosynthetic attenuation by KPT-9274, while critical for highly proliferative cancer cells, does not appear to be important in the slower growing cystic epithelial cells during cystogenesis. KPT-9274 was not toxic in our ADPKD animal model or in other cancer models. Thus, this small molecule inhibitor could be evaluated in a clinical trial as a viable therapy of ADPKD

Midbody: from cellular junk to regulator of cell polarity and cell fate

At late mitosis, the mother cell divides by the formation of a cleavage furrow, leaving two daughter cells connected by a thin intercellular bridge. During ingression of the cleavage furrow, the central spindle microtubules are compacted to form the structure known as the midbody (MB). The MB is situated within the intercellular bridge, with the abscission site sometimes occurring on one side of the MB. As a result of this one-sided (asymmetric) abscission, only one daughter cell can inherit the post-mitotic MB. Interestingly, recent studies have identified post-mitotic MBs as novel signaling platforms regulating stem cell fate and proliferation. Additionally, MBs were proposed to serve a role of polarity cues during the neurite outgrowth and apical lumen formation. Thus, abscission and MB inheritance is clearly a highly regulated cellular event that can affect development and various other cellular functions. In this review we discuss the latest findings regarding post-mitotic MB functions, as well as the machinery regulating MB inheritance and accumulation