Proteomic Profiling of Recurrent Colorectal Cancer Reveals RICTOR with Cancer-Promoting Role by Downregulating Mitochondrial Oxidative Phosphorylation

Zhenyu Jia, Yongda Lu, Lu Zheng, Jiaqing Shen, Chenyue Tang, Yuqi Shi, Lijuan Qian, Tingting Xia

Article ID: 7895
Vol 38, Issue 3, 2024
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20243803.164
Received: 20 March 2024; Accepted: 20 March 2024; Available online: 20 March 2024; Issue release: 20 March 2024

Abstract

Background: Colorectal cancer (CRC), ranking as the second leading cause of global cancer-related deaths, is marked by a high recurrence rate. Metabolic reprogramming, a characteristic feature of CRC, involves a shift from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis to fuel cell proliferation. However, the regulatory mechanisms of OXPHOS in CRC recurrence remain unclear. Methods: Proteomic analysis was conducted using CRC tissues from recurrent and non-recurrent patients. Candidate proteins identified through bioinformatic analysis were validated using Real-time quantitative PCR and western blot. Functional investigations were carried out through knockdown and overexpression strategies. Results: Our study revealed a correlation between CRC recurrence and reduced OXPHOS levels. Meanwhile, an upregulation of rapamycin-insensitive companion of mTOR (RICTOR) was observed in recurrent patients, correlating with a poorer CRC prognosis. RICTOR inhibited the expression of subunits of OXPHOS complexes, including NADH-ubiquinone oxidoreductase core subunit V2 (NDUFV2), NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUFB8), succinate dehydrogenase complex, subunit B (SDHB), and cytochrome c oxidase 5A (COX5A). Overexpression of RICTOR suppressed mitochondrial OXPHOS and promoted cell proliferation. Conversely, RICTOR knockdown reversed enhanced cell proliferation and inhibited subcutaneous tumor growth. Conclusion: In summary, our findings suggest that elevated RICTOR expression disrupts the assembly of the mitochondrial electron respiratory chain, consequently suppressing OXPHOS levels and ultimately promoting CRC recurrence.


Keywords

colorectal cancer;oxidative phosphorylation;RICTOR;mitochondrial complex


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