COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers

Abstract

Oxidative phosphorylation (OXPHOS) consists of four enzyme complexes and ATP synthase, and is crucial for maintaining physiological tissue and cell growth by supporting the main bioenergy pool. Cytochrome c oxidase (COX) has been implicated as a primary regulatory site of OXPHOS. Recently, COX subunit 5B (COX5B) emerged as a potential biomarker associated with unfavorable prognosis by modulating cell behaviors in specific cancer types. However, its molecular mechanism remains unclear, particularly in colorectal cancers (CRCs). To understand the role of COX5B in CRCs, the expression and postoperative outcome associations using independent in-house patient cohorts were evaluated. A higher COX5B tumor/nontumor expression ratio was associated with unfavorable clinical outcomes (p = 0.001 and 0.011 for overall and disease-free survival, respectively. In cell-based experiments, the silencing of COX5B repressed cell growth and enhanced the susceptibility of CRCs cells to anticancer drugs. Finally, downstream effectors identified by RNA sequencing followed by RT-qPCR and functional compensation experiments revealed that the tight junction protein Claudin-2 (CLDN2) acts downstream of COX5B-mediated bioenergetic alterations in controlling cell growth and the sensitivity to anticancer drugs in CRCs cells. In conclusion, it was found that COX5B promoted cell growth and attenuated anticancer drugs susceptibility in CRCs cells by orchestrating CLDN2 expression, which may contribute to unfavorable postoperative outcomes of patients with CRCs.

Long-Chain Acyl Coenzyme A Dehydrogenase, a Key Player in Metabolic Rewiring/Invasiveness in Experimental Tumors and Human Mesothelioma Cell Lines

“…Our results agreed with previously published literature on the impact of its high expression on tumor invasiveness and poor prognosis in patients with breast cancer [43]. More recently, further insights have confirmed its tremendous role as a growth-promoting gene, both in hepatoma [44] and colorectal cancer [45]. Interestingly, the combined upregulation of COX5B and ATP5H was also reported by Yusenko et al in renal oncocytomas [19].…”

Valine improves mitochondrial function and protects against oxidative stress

“…Mitochondria play a predominant role in regulating energy metabolism, ATP production and oxygen consumption and for the maintenance of cellular functions (Chu et al. 2021 ). The increased OCR is an important indicator, which reflects the mitochondrial respiratory chain complex activity (du Plessis et al.…”

Integrative Analysis of Bulk RNA-Seq and Single-Cell RNA-Seq Unveils Novel Prognostic Biomarkers in Multiple Myeloma

“…Wang et al also reported that COX6C is a negative prognostic biomarker in MM [ 46 ]. Similar to COX6C, COX5B was found to promote cell growth and reduce anticancer drug susceptibility in colorectal cancer cells, which may lead to unfavorable postoperative outcomes for patients with colorectal cancer [ 47 ]. Bioenergetic alteration-dependent activation of AMPK was found to occur in hepatoma cells via COX5B regulation of UHMK1 expression [ 48 ].…”