Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients

Abstract

MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal-specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion-associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine-induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and γ-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients.

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

“…Hepatic stellate cells become activated to enhance the production of cellular fibronectin while the clearance of cellular fibronectin by hepatocytes is impaired so that more fibronectins are accumulated, which eventually leads to liver fibrosis and regeneration (Zhang & Friedman, 2012). As we previously reported, autophagy is required to be enhanced because of the high metabolic stress induced by genome instability in tumor foci (Xie et al ., 2011b; Jiang et al ., 2015). In response to the high requirement of autophagy activity, MAP1S is elevated in such tumor foci (Xie et al ., 2011b; Jiang et al ., 2015).…”

“…As we previously reported, autophagy is required to be enhanced because of the high metabolic stress induced by genome instability in tumor foci (Xie et al ., 2011b; Jiang et al ., 2015). In response to the high requirement of autophagy activity, MAP1S is elevated in such tumor foci (Xie et al ., 2011b; Jiang et al ., 2015). If tumor cells are not capable of providing sufficient MAP1S to promote autophagy flux to meet the demand, they may induce pyroptosis to impair the survival of themselves and their host cells.…”

“…If tumor cells are not capable of providing sufficient MAP1S to promote autophagy flux to meet the demand, they may induce pyroptosis to impair the survival of themselves and their host cells. It is possibly the reason that prostate cancer patients with lower levels of MAP1S in their tumor tissues had a shorter time of survival than the patients with high levels of MAP1S (Jiang et al ., 2015). …”

“…Oxidative stress in turn activates NLRP3 inflammasome and eventually induces an inflammatory form of cell death referred to as pyroptosis that promotes the mortality and impair the survival of host structural, hematopoietic, and immune‐competent cells (Lamkanfi & Dixit, 2014; Ryter et al ., 2014; Terlizzi et al ., 2014; Yu et al ., 2014). Cancer patients with defective autophagy live a short lifespans (Jiang et al ., 2014, 2015). Both calorie restriction and pharmacologic agents that mimic the impact of calorie restriction induce autophagy and prolong lifespans (Madeo et al ., 2015).…”

Expression Profile of Autophagy-related Markers in Localized Prostate Cancer: Correlation With Biochemical Recurrence After Radical Prostatectomy

“…8,9 In recent years, there have been several studies reporting that the expression profiles of molecular markers consisting of the autophagy pathway could be used as useful predictors of clinical courses in several types of human malignant tumor [10][11][12][13][14] ; however, limited information is available on the prognostic significance of autophagy-related proteins in patients with PC. [15][16][17] Considering these findings, we evaluated the expression patterns of multiple autophagy-related proteins, including autophagy-related gene 5 (Atg5), autophagyrelated gene 9 (Atg9), Beclin1, microtubule-associated protein light chain 3 (LC3), and UNC-51elike kinase 1 (ULK1), in RP specimens from 160 patients with localized PC to analyze the prognostic significance of these markers in this cohort of patients.…”