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

Liu, Bing; Nishikawa, Masatomo; Tei, Hiromoto; Fujisawa, Masato

doi:10.1016/j.urology.2015.03.006

Cited by 12 publications

(10 citation statements)

References 27 publications

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“…6B ) clinical cohorts. Consistent with these clinical correlations, previous histological studies have linked high ULK1 levels to biochemical recurrence and PSA levels ( 57 , 58 ). Unfortunately, the ULK1 antibody used in these studies is no longer commercially available and validation studies using other commercially available ULK1 or p-ULK1(S555) antibodies revealed these antibodies were not suitable for ICC/IF or IHC ( Supplementary Figs.…”

Section: Resultssupporting

confidence: 76%

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

et al. 2021

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Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca 2+ /calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5’-AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1), but independent of canonical mechanistic target of rapamycin (mTOR) activity. Increased CAMKK2-AMPK-ULK1 signaling correlated with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Similarly, an inhibitor of AMPK-ULK1 blocked autophagy, cell growth and colony formation in prostate cancer cells. Collectively, our findings converge to demonstrate that AR can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Thus, this pathway may represent an alternative autophagic target in CRPC.

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Section: Resultssupporting

confidence: 76%

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

et al. 2021

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“…In addition, recent studies revealed upregulation of LRPPRC in a variety of human malignancies, and its association with tumorigenesis 23. Only one study investigated the role of ULK1 in PCa and found that ULK1 expression is independently associated with BCP in localised PCa after radical prostatectomy; however, patients with metastatic PCa were not included in the study 24. In addition, ULK1 also has been found to be upregulated in human oesophageal squamous cell carcinoma and breast cancer, and may serve as a marker for poor prognosis in these malignancies 20 25 26.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of autophagy-related marker ULK1 and mitochondrion-associated autophagy inhibitor LRPPRC are associated with biochemical progression and overall survival after androgen deprivation therapy in patients with metastatic prostate cancer

Zhang

et al. 2016

J Clin Pathol

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“…Liu et al just recently evaluated the prognostic impact of 5 autophagy markers on the clinical endpoint of BCR after radical prostatectomy and reported no association for LC3b in agreement with our results. Yet, an association of positive UNC-51-like kinase 1 (ULK1) reactivity with BCR was reported after a relatively short median follow-up of 51 months [ 26 ]. In the present study, no association of autophagy with BCR rates could be observed.…”

Section: Discussionmentioning

confidence: 99%

Negative LC3b immunoreactivity in cancer cells is an independent prognostic predictor of prostate cancer specific death

et al. 2017

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BackgroundAutophagy is a catabolic cellular process used for degradation of cytoplasmic organelles and preservation of cell viability. In this study we aimed to analyse the level of autophagy markers in benign and malignant prostate tissue and to evaluate the prognostic properties for patients with prostate cancer (PCa).ResultsLC3b expression was significantly upregulated in PCa, especially in metastatic and castration-resistant PCa samples compared to benign prostate tissue (p<0.001). Evaluation of expression in malignant radical prostatectomy specimens revealed an inverse association with preoperative serum PSA levels (p=0.02) and Gleason Score (p=0.07). LC3b immunoreactivity was identified as a novel predictor of PCa specific death after radical prostatectomy, independent of Gleason score, tumour stage, and surgical margin status in a multivariable cox regression analysis (hazard ratio 0.09, 95% confidence interval 0.01-0.69, p=0.021). A significant association of ATG-5 and Beclin 1 with LC3b expression could be noticed (p<0.001), but no link with other clincopathologic parameters was observed.Materials and MethodsA Tissue microarray containing 468 formalin-fixed, paraffin-embedded prostate tissue cores was stained immunohistochemically for major autophagy proteins LC3b, ATG5 and Beclin 1. Immunoreactivity was semiquantitatively scored and correlated with pathologic and clinical parameters, including tumour stage, Gleason score, preoperative PSA level, biochemical recurrence rate and survival. The median clinical follow-up was 132 months.ConclusionLC3b was significantly overexpressed in malignant compared to benign prostate tissue. However, positive LC3b immunoreactivity in PCa, as a marker of increased autophagy, was independently associated with a reduced disease-specific mortality.

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

Cited by 12 publications

References 27 publications

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

Elevated levels of autophagy-related marker ULK1 and mitochondrion-associated autophagy inhibitor LRPPRC are associated with biochemical progression and overall survival after androgen deprivation therapy in patients with metastatic prostate cancer

Negative LC3b immunoreactivity in cancer cells is an independent prognostic predictor of prostate cancer specific death

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