Oncogenic role of copper‑induced cell death‑associated protein DLD in human cancer: A pan‑cancer analysis and experimental verification

Abstract

Copper ions can bind directly to lipoylated components of the tricarboxylic acid (TCA) cycle, triggering the aggregation of mitochondrial lipoylated proteins and the destabilization of Fe-S cluster proteins, resulting in copper-dependent cell death. Dihydrolipoamide dehydrogenase (DLD) is a key protein of the TCA cycle and constitutes the E3 component of the α-ketoglutarate dehydrogenase complex, which is deeply interconnected with the mitochondrial electron transfer chain in the TCA cycle. Tumor cells demonstrate dependency on glutaminolysis fuelling to carry out the TCA cycle and essential biosynthetic processes supporting tumor growth. Therefore, DLD plays an important role in the tumor biological process. However, to the best of our knowledge, no pan-cancer analysis is currently available for DLD. Therefore, the present study first explored the DLD expression profile in 33 tumors in publicly available datasets, including TIMER2, GEPIA2, UALCAN, cBioPortal and STRING. TIMER2, GEPIA2 and UALCAN were used for exploring gene expression; survival prognosis was detected by GEPIA2; genetic alteration was analysed by cBioPortal; immune infiltration data was obtained from TIMER2; interacting proteins of DLD were detected by STRING. DLD was found to be highly expressed in colon, liver, lung, stomach, renal, corpus uteri endometrial and ovarian cancers compared with normal tissues, and its high expression was associated with poorer prognosis in ovarian cancer. To the best of our knowledge, the present study provided the first comprehensive pan-cancer analysis of the oncogenic role of DLD across different tumors types. As the expression of DLD in ovarian cancer was high, and high expression is associated with poor prognosis, experimental verification of DLD in ovarian cancer was conducted. In the present study, DLD expression was found to be high in the ovarian cancer OC3 cell line, compared with the normal ovarian epithelial IOSE80 cell line by reverse transcription-quantitative PCR analysis. After knockdown of DLD expression, it was found that DLD regulated metabolic pathways by suppressing the intracellular NAD + /NADH ratio, which then in turn suppressed tumor cell proliferation detected by MTT assay. In conclusion, the present pan-cancer analysis of DLD demonstrated that DLD expression was associated with the clinical prognosis, immune infiltration and tumor mutational burden in 33 tumor types, and experimental verification in ovarian cancer was conducted. These results may contribute to the understanding of the role of DLD in tumorigenesis.

Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy

“…A representation of these distinct characteristics is shown in Table 1. Disruption of copper homeostasis, and oxidative stress FDX1 [23] DLAT [23] DBT [23] GCSH [23] DLST [23] LIAS [23] CTR1 [23] ATP7A/ATP7B [24] MT [24] GSH [24] PDH [25] PDHA1 [25] PDHB [25] KDH [26] SLC31A1 [27,28] LIPT1 [29] DLD [30] Neurological diseases (e.g., Menkes and Wilson) [26]. Cancer (e.g., elevated serum copper levels in oral, gallbladder, liver, breast, esophageal, pancreatic, bladder, renal, prostatic, thyroid, cervical, and lung; decreased serum copper levels in endometrial and colorectal) [10,31].…”

“…The primary factor contributing to Wilson disease is a mutation in the ATP7B gene, a crucial copper transport protein responsible for biliary copper excretion [122]. Mutations in this gene result in the abnormal accumulation of copper in both the liver and brain [30]. Compared to many neurogenetic diseases, Wilson disease responds well to treatment during both its acute and chronic stages [123].…”