Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway

Abstract

Aim. The aim of this study was to investigate the effect and underlying pathway of pyrroline-5-carboxylate reductase-2 (PYCR2) on colorectal cancer (CRC). Methods. The Cancer Genome Atlas (TCGA) database was used to analyze PYCR2 expression levels and clinical information. Cell proliferation was evaluated using colony forming and EdU assay. Cell apoptosis rate was determined using flow cytometry. Cell migration and invasion were measured by performing a Transwell assay, and PYCR2, MMP-2, MMP-9, Bax, cleaved caspase-3, Bcl-2, cleaved PARP, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR protein levels were detected by Western blot. Results. A review of the TCGA database revealed that PYCR2 was highly expressed in CRC patients and that high PYCR2 expression was associated with advanced stage, adenocarcinoma, nodal metastasis, and poor survival rate. Moreover, PYCR2 knockdown reduced cell viability, proliferation, migration, and invasion and increased apoptosis. Additionally, PYCR2 knockdown increased Bax, cleaved caspase-3, and cleaved PARP levels and decreased Bcl-2, MMP-2, MMP-9, p-PI3K, p-AKT, and p-mTOR levels in CRC cells. Effects of silencing PYCR2 on proliferation, migration, invasion, apoptosis, and the PI3K/AKT/mTOR pathway in CRC cells were all reversed using a PI3K activator (740Y-P). Conclusion. PYCR2 was highly expressed in CRC, and its knockdown suppressed CRC tumorigenesis via inhibiting the activation of PI3K/AKT/mTOR pathway. This finding provides a new theoretical foundation for the treatment of CRC.

The Prognostic Roles of PYCR2 and ZBTB18 Expression in Tissues of Colorectal Carcinoma and Non-Neoplastic Tissues: An Immunohistochemical Study

“…Our results were in line with those of Yin et al, 13 who were the first to investigate the genetic roles of PYCR2 in CRC oncogenesis, progression and shortened OS. Additionally, our results are similar to those of Wang et al, 7 who assessed the genetic and tissue protein expression of PYCR2 in CRC and other tumor types, and found that levels of PYCR2 are upregulated in CRC tumor tissues at the mRNA and protein levels.…”

“…Another role of PYCR2 has been studied in CRC metastases, by the activation of matrix metalloproteinases (MMPs), which mediate CRC cell invasion and migration through degradation of the extracellular matrix (ECM). 13,23 All of the aforementioned results and those of current study show that the upregulation of PYCR2 could lead to CRC progression and metastases through several mechanisms that need to be clarified. To clarify role of PYCR2 in CRC, we assessed the levels of another biomarker, ZBTB18, in sections from CRC and adjacent non-neoplastic tissues of the colonic mucosa.…”

“…The detection of predictive and prognostic biomarkers and novel targeting therapies for CRC is important to improve its prognosis. 13 Proline metabolism and its resulting products are important for many biological processes which occur in normal and oncogenic processes that lead to the development and progression of many cancers. [14][15][16] A proline family member, PYCR2 has been studied, and was found to have many roles in the progression of cancers of various organs, but its role in the oncogenesis and progression of CRC has not been sufficiently studied.…”

“…Another role of PYCR2 has been studied in CRC metastases, by the activation of matrix metalloproteinases (MMPs), which mediate CRC cell invasion and migration through degradation of the extracellular matrix (ECM). 13 23…”

“…19,20 PYCR2 has been found to be correlated with MYC levels in CRC, and MYC knockdown leads to a reduction in the growth, progression and metastasis of CRC. 21,22 Yin et al, 13 demonstrated the roles of PYCR2 in apoptosis in CRC as its silencing could induce cell apoptosis by increasing the levels of proapoptotic factors and decreasing the levels of antiapoptotic factors. Another role of PYCR2 has been studied in CRC metastases, by the activation of matrix metalloproteinases (MMPs), which mediate CRC cell invasion and migration through degradation of the extracellular matrix (ECM).…”