Loading‐induced antitumor capability of murine and human urine

Abstract

While urine has been considered as a useful bio‐fluid for health monitoring, its dynamic changes to physical activity are not well understood. We examined urine's possible antitumor capability in response to medium‐level, loading‐driven physical activity. Urine was collected from mice subjected to 5‐minute skeletal loading and human individuals before and after 30‐minute step aerobics. Six cancer cell lines (breast, prostate, and pancreas) and a mouse model of the mammary tumor were employed to evaluate the effect of urine. Compared to urine collected prior to loading, urine collected post‐activity decreased the cellular viability, proliferation, migration, and invasion of tumor cells, as well as tumor weight in the mammary fat pad. Detection of urinary volatile organic compounds and ELISA assays showed that the loading‐conditioned urine reduced cholesterol and elevated dopamine and melatonin. Immunohistochemical fluorescent images presented upregulation of the rate‐limiting enzymes for the production of dopamine and melatonin in the brain. Molecular analysis revealed that the antitumor effect was linked to the reduction in molecular vinculin‐linked molecular force as well as the downregulation of the Lrp5‐CSF1‐CD105 regulatory axis. Notably, the survival rate for the high expression levels of Lrp5, CSF1, and CD105 in tumor tissues was significantly lowered in the Cancer Genome Atlas database. Collectively, this study revealed that 5‐ or 10‐minute loading‐driven physical activity was sufficient to induce the striking antitumor effect by activating the neuronal signaling and repressing cholesterol synthesis. The result supported the dual role of loading‐conditioned urine as a potential tumor suppressor and a source of diagnostic biomarkers.

Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1

“…Of note, in our previous study, mechanical stimulation was shown to downregulate CSF1, macrophage colony-stimulating factor, and CD105, a tumor-promoting glycoprotein in the urine. 14 The present study demonstrated that daily loading for 5 minutes (600 bouts per day) prevented tumor progression not only at the loaded site but also at a remote site at the mammary fat pad. The beneficial loading effect was accompanied by the downregulation of Runx2, MMP9, and Snail in the bone marrow of the loaded tibia, as well as the metabolic VOC changes in the mevalonate pathway for cholesterol synthesis.…”

“…Collectively, mechanical stimulations presented local and global antitumor effects in the mouse model of breast cancer, and step aerobics by human subjects supported the loading‐driven regulation of WISP1 in urinary metabolism. Of note, in our previous study, mechanical stimulation was shown to downregulate CSF1, macrophage colony‐stimulating factor, and CD105, a tumor‐promoting glycoprotein in the urine 14 …”

“…We have also shown that axial tibia loading in a mouse model or step aerobics in human subjects can sharply reduce the level of cholesterol and elevate the levels of dopamine and melatonin in urine, in which dopamine and melatonin serve as tumor-suppressing agents. 14 Although mechanical stimulations were shown to convert urine into an antitumor agent, the mechanical effects with knee loading on the growth of mammary tumors and loaded tumor-invaded bones have not been elucidated.…”

Tracking the Progression of Triple Negative Mammary Tumors over Time by Chemometric Analysis of Urinary Volatile Organic Compounds

“…Ketones and other carbonyls have been reported to be markers for prostate cancer [ 16 , 18 ], lung cancer [ 44 , 45 ] and diabetes [ 46 ]. Another study by the authors showed two ketones reported in this study, 2-HEP and 2-PEN, were enriched in urine samples collected from mice receiving an antitumoral treatment [ 47 ] (treatment was bone loading, a simulated form of exercise). Furthermore, in vitro analyses showed upon treatment with 2-HEP and 2-PEN, hypothalamic neuronal cells had reduced tumor cell viability accompanied with elevated levels of aralkylamine N-acetyltransferase (AANAT) and tyrosine hydrogenase (TH).…”

“…Furthermore, in vitro analyses showed upon treatment with 2-HEP and 2-PEN, hypothalamic neuronal cells had reduced tumor cell viability accompanied with elevated levels of aralkylamine N-acetyltransferase (AANAT) and tyrosine hydrogenase (TH). AANAT and TH are rate-limiting enzymes that produce melatonin and dopamine, which have been shown to have a role in tumor suppression [ 47 ]. These studies show the potential antitumor capability of ketones, which is intriguing as they were downregulated by mammary tumors in this study.…”