PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Abstract

BackgroundChronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation.MethodsThe animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues.ResultsAOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm2, which was significantly decreased to 5.85 ± 0.95 mm2 by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer.ConclusionsPersistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.

Branched-Chain Amino Acid Degradation Pathway was Inactivated in Colorectal Cancer: Results from a Proteomics Study

“…A mouse model was established using AOM/DSS treatment to identify proteins related to colon cancer, as depicted in Figure 1 A and as previously described 8 . The total duration of the study was 15 weeks and two days, including one week of free feeding, 14 weeks for model development, and two days between capsule endoscopy and euthanasia.…”

“…Patients with inflammatory bowel disease (IBD) have an increased risk of developing CRC [4,5]. To investigate the underlying mechanisms and potential biomarkers of colon cancer, researchers have developed animal models that induce tumor growth through inflammation by utilizing substances, such as azoxymethane (AOM) and dextran sulfate sodium (DSS) [6][7][8]. AOM, a well-established carcinogen, creates DNA adducts [9], whereas DSS serves as an inflammatory agent that damages the epithelial lining of the colon [10].…”

Identification and validation of a genetic risk signature associated with prognosis in clear-cell renal cell carcinoma patients

“…[40] PDIA2 plays a role in the folding of nascent proteins in the ER to regulate signaling. [41] PLA2G6 can mediate apoptosis and premature degeneration of dopaminergic neurons in the substantia nigra. [42,43] Meanwhile, ROC-AUC estimates indicated that the prognostic features exhibited by ERSGRS performed favorably.…”