Significance: TNF receptor-associated protein (TRAP1) is found predominantly in mitochondria. A possible direct impact of TRAP1 on mitochondrial metabolism remains unexplored. We used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1 deficiency promotes increased mitochondrial respiration, fatty acid oxidation, tricarboxylic acid cycle intermediates, ATP and reactive oxygen species, while concomitantly suppressing glucose metabolism. TRAP1 deficiency also results in strikingly enhanced cell motility and invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes.

Sarcopenia, a novel concept reflecting the degenerative loss of skeletal muscle mass, is an objective indicator of cancer cachexia. We investigated its role as a prognostic biomarker in advanced urothelial carcinoma (UC) patients. This retrospective study consisted of 88 UC patients with cT4 and/or metastases to lymph nodes/distant organs. Skeletal muscle index (SMI), an indicator of whole-body muscle mass, was measured from computed tomography (CT) images at the diagnosis. Sarcopenia was defined as SMIs of <43 cm²/m² for males with body mass index (BMI) <25 cm²/m², <53 cm²/m² for males with BMI ≥25 cm²/m², and <41 cm²/m² for females. Predictors of overall survival (OS) were examined using Cox proportional hazard models. Sixty-seven patients (76%) died during the median follow-up of 13 months. The median OS rate was 13 months. Multivariate analysis revealed that SMI was a significant and independent predictor of shorter OS (hazard ratio (HR) 0.90, P <0.001). In the present cohort, 53 (60%) were diagnosed with sarcopenia. The median OS rates were 11 and 31 months for sarcopenic and non-sarcopenic patients, respectively (P <0.001). On multivariate analysis, sarcopenia was a significant and independent predictor of shorter OS (HR 3.36, P <0.001), along with higher C-reactive protein (CRP) (P = 0.001), upper urinary tract cancer (P = 0.007), higher lactate dehydrogenase (LDH) (P = 0.047), and higher alkaline phosphatase (ALP) (P = 0.048). Sarcopenia, which is readily evaluated on routine CT scans, is a useful prognostic biomarker of advanced UC. Non-sarcopenic patients can expect long-term survival. Evaluating sarcopenia can be helpful for decision-making processes in the management of advanced UC patients.

Sarcopenia, a novel concept reflecting the degenerative loss of skeletal muscle mass, is a critical physiological change during the development of cancer cachexia. We retrospectively investigated the prognostic role of sarcopenia in patients with metastatic renal cell carcinoma. Skeletal muscle index was calculated using computerized tomography performed at the diagnosis of metastatic renal cell carcinoma. Sarcopenia was defined as skeletal muscle index less than 43 cm(2)/m(2) for males with a body mass index less than 25 kg/m(2), less than 53 cm(2)/m(2) for males with a body mass index 25 kg/m(2) or greater, and less than 41 cm(2)/m(2) for females. The relationship between sarcopenia and overall survival was assessed in 92 patients with metastatic renal cell carcinoma using Cox proportional hazards models. The predictive accuracy of these models was evaluated using the c-index. A total of 63 (68%) patients were classified as having sarcopenia and 52 (57%) died (median overall survival 27 months) during followup (median 19 months). A multivariate analysis identified sarcopenia as a significant and independent predictor of overall survival (HR 2.58, p = 0.015), along with prior nephrectomy (p <0.001), number of metastatic sites (p = 0.017), corrected calcium (p = 0.026) and lactate dehydrogenase (p = 0.006). The 3-year overall survival rates were 31% and 73% for sarcopenic and nonsarcopenic cases, respectively (p <0.001). The integration of sarcopenia into the Memorial Sloan Kettering Cancer Center risk model improved the c-index from 0.726 to 0.758 (addition of sarcopenia to the original model) and 0.755 (substitution of sarcopenia for Karnofsky performance status). Sarcopenia is a significant prognostic factor in metastatic renal cell carcinoma.