PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Abstract

Background Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. Methods The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation. Results PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway. Conclusions PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

LINC00924-induced fatty acid metabolic reprogramming facilitates gastric cancer peritoneal metastasis via hnRNPC-regulated alternative splicing of Mnk2

“…We next investigated which signaling pathway might contribute to LINC00924-induced PPARα activation. Previous studies outlined a regulatory role for the JNK and ERK and p38 MAPK signaling pathways in regulating PPARα expression [ 23 – 26 ]. Therefore, we examined protein levels of the JNK, ERK and phosphorylated p38 (p-p38) MAPK in MGC803-NC/LINC00924-OE and AGS-NC/LINC00924-KD cells.…”

Schisantherin A inhibits cell proliferation by regulating glucose metabolism pathway in hepatocellular carcinoma

“…Further transcriptome sequencing and KEGG signaling pathway enrichment data showed that the metabolic process in Hep3B cells treated with STA had changed. Growing evidence suggests that metabolic disorder is a significant hallmark of malignant tumors that controls key tumor biological processes such as the proliferation, migration, and invasion of tumor cells ( Dai et al, 2022 ; Sun et al, 2022 ; Tan et al, 2022 ). Thus, by inhibiting the metabolic pathways of tumor cells, the occurrence and development of tumors could be prevented.…”

The remodeling roles of lipid metabolism in colorectal cancer cells and immune microenvironment

“…As a member of PTPs (protein tyrosine phosphatases), PTPRO (protein tyrosine phosphatase receptor type O) has been revealed that PTPRO expression is notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation is associated with poor prognosis of patients with CRC. PTPRO silencing induced the activation of the AKT/mTOR signaling axis, thus promoting de novo lipogenesis by enhancing the expression of SREBP1 and its target lipogenic enzyme ACC1 by activating the AKT/mTOR signaling pathway [69].…”

“…As a member of PTPs, the role of PTPRO in cell signal transduction has attracted more and more attention. It has been proved that PTPRO attenuation is achieved by suppressing PPAR α and its downstream enzyme, peroxidase acyl coenzyme A oxidase 1 (ACOX1), to reduce FA oxidation rate [69]. High expression PPARβ/δ is closely related to the occurrence and development of colorectal cancer.…”