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Introduction: Despite widespread usage, research on the relationship of marijuana use to disease is sorely lacking. We sought to test the relationship of LUTS/BPH treatment and endocannabinoid agonist usage, as well as alcohol usage and depression, with treatment for LUTS/BPH in our health system., Materials and Methods: We queried our hospital system database of nearly three million patients in a marijuana-legalized region for data from the electronic medical record between January 2011 and October 2018. Men over the age of 45 on medical therapy for LUTS (selective alpha blockade and/or finasteride) were included. Exclusions were diagnosis of bladder or prostate malignancy and men with only one visit. Alcohol and marijuana (MJ) use were found from diagnosis code and/or social history text. Medical diagnoses were based on ICD-9/10 codes. Multiple logistic regression was used to control for confounders. We considered all men over the age of 45 who had any of these features: depression, obesity or metabolic syndrome (MetS), hypertension (HTN), erectile dysfunction (ED), hypogonadism, diabetes (DM) and calculated the odds ratio of also receiving medical therapy for LUTS. Univariable and multivariable analyses were employed, multiple logistic regression was used to control for confounders., Results: A total of 173,469 patients were identified meeting criteria with 20,548 (11.9%) on medical treatment for LUTS. After adjusting for confounding variables, MJ and depression remained associated with an increased risk of LUTS medication, within the context of verifying previously established relationships of ED, Obesity/MetS, DM, HTN and hypogonadism., Conclusions: Men with depression and MJ usage were more likely to be treated for LUTS/BPH in our system. Better understanding of the causality of this relationship and potential interaction of LUTS/BPH with the endocannabinoid system is desirable.

Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, O -GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the "chaperone code.", Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Backe et al.)

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating" mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)