PYCR1 is associated with papillary renal cell carcinoma progression

Abstract

<jats:title>Abstract</jats:title><jats:sec id="j_med-2019-0066_s_005_w2aab3b7d354b1b6b1aab1c16b1Aa"><jats:title>Objective</jats:title><jats:p>We aimed to determine the function of pyrroline-5-carboxylate reductase 1 (PYCR1) on progression of papillary renal cell carcinoma (PRCC) and related mechanism.</jats:p></jats:sec><jats:sec id="j_med-2019-0066_s_006_w2aab3b7d354b1b6b1aab1c16b2Aa"><jats:title>Methods</jats:title><jats:p>The TCGA database provided us expression profiles of PYCR1 and overall survival rates. Small interfering RNA (siRNA) was used to knockdown PYCR1; quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were conducted to identify the expression levels of mRNA and protein. The cell counting kit-8 (CCK-8) and colony formation assays were used to explore cell viability in Ketr-3 cells. The migration and invasion of Ketr-3 cells were investigated by transwell assays.</jats:p></jats:sec><jats:sec id="j_med-2019-0066_s_007_w2aab3b7d354b1b6b1aab1c16b3Aa"><jats:title>Results</jats:title><jats:p>We found that PYCR1 was over-expressed in PRCC tissues and cells, causing poor outcomes. Moreover, reduction of PYCR1 played a negative role on cell proliferation, migration and invasion in tumor cells. The important Akt/mTOR pathway proteins, phosphorylated Akt (p-Akt) and phosphorylated mTOR (p-mTOR), also showed lower levels compared with control groups.</jats:p></jats:sec><jats:sec id="j_med-2019-0066_s_008_w2aab3b7d354b1b6b1aab1c16b4Aa"><jats:title>Conclusion</jats:title><jats:p>These findings showed that disordered expression of PYCR1 could modulate PRCC progression through the Akt/mTOR pathway, implying a theoretical basis for PYCR1 as a potential therapeutic target in future clinical PRCC treatment.</jats:p></jats:sec>

The Janus-like role of proline metabolism in cancer

“…In melanoma cells, knockdown of PYCR1 causes decreased activity of the Akt pathway and reduces the expression of RAPTOR, suggesting a downstream inhibition of protein synthesis 96 . Similarly, RNA-interference suppression of PYCR1 decreases levels of activated phospho-Akt and activated phospho-mTOR in renal cancer cells 103 .…”

“…In some instances, PYCR1 expression is a reliable diagnostic biomarker which predicts poor prognosis in patients with melanoma 96 , breast cancer 64,101 , renal cell cancers 100,103 , and NSCLC 98 . Studies that employed genetic depletion of PYCR1 have confirmed a functional role for PYCR1 in promoting tumor progression and cancer cell survival in colorectal cancer cells 104 , NSCLC cells 42,97,98 , renal cancer cells 64,103 , prostate cancer cells 105 , and IDH1-mutant gliomas 106 .…”

“…Indeed, PYCR1 expression is increased in metastatic breast cancer. Its genetic depletion in breast, lung cancer, renal carcinoma cells, and melanoma reduces cells' ability to migrate and invade in in vitro essays 96,99,101,103 . In addition, supplementing L-proline in the culture medium stimulates proliferation and induces a mesenchymal invasive phenotype in mouse embryonic stem cells (mESCs) 152,153 .…”

Proline Metabolism in Tumor Growth and Metastatic Progression

“…PYCR1 is highly expressed also in prostate cancer tissues (33), in renal cell carcinoma (RCC) (34), in papillary renal cell carcinoma (PRCC) (35) and in human malignant melanoma (MM) (36). These studies showed that PYCR1 expression strongly influence cell behavior (proliferation, colony formation, apoptosis) in different cancer contexts, and correlate with poor outcome and decreased overall survival in patients.…”

“…These studies showed that PYCR1 expression strongly influence cell behavior (proliferation, colony formation, apoptosis) in different cancer contexts, and correlate with poor outcome and decreased overall survival in patients. Of particular interest is the finding that PYCR1 ablation inhibits migration and invasion both in PRCC and MM cells, altering phosphorylation of AKT (36) and mTOR (35).…”