Connexins and Glucose Metabolism in Cancer

Abstract

Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.

Comprehensive Pan-Cancer Analysis of Connexin 43 as a Potential Biomarker and Therapeutic Target in Human Kidney Renal Clear Cell Carcinoma (KIRC)

“…Recently, Cx43 has been characterized as a valuable diagnostic and prognostic biomarker in various cancers [14]. In our study, we employed ROC curve analysis and Kaplan-Meier survival curve analysis to assess the diagnostic and prognostic significance of GJA1 in pan-cancer.…”

“…Fragmented forms of Cx43 have been implicated in exerting a vital role in the regulation of gene transcription and cell growth [11][12][13]. In addition, Cx43 expression has been observed to be associated with both cancer promotion and suppression, exerting significant influences on carcinogenesis, cancer progression, and metastasis [14]. For example, previous studies have shown that Cx43 expression was significantly decreased in gastric cancer, melanoma cancer [15], pancreatic cancer [16,17], lung cancer [18,19], chronic B-cell leukemia [20], prostate cancer [21], breast cancer [22][23][24][25], and thyroid cancer [9].…”

The emerging role of long non-coding RNAs in renal cell carcinoma progression and clinical therapy via targeting metabolic regulation

“…However, compared with the oxidative phosphorylation pathway, the conversion of glucose to lactic acid produces less energy. It is insufficient to maintain the energy supply for cancer cells, and then more glucose will be consumed ( Chakraborty et al, 2021 ; Jones and Bodenstine, 2022 ). The kidneys contain a large number of glucose transporters, which participate in glucose reabsorption, excretion and other metabolic pathways.…”

“…Once VHL is lost, the degradation process of transcription factors will be weakened. And then HIF-1α transcription factors under normoxic conditions will be accumulated, and makes cells in a pseudohypoxic state, leading to the changes in the metabolic process ( Appelhoff et al, 2004 ; Chatzopoulos et al, 2022 ; Chen et al, 2022a ; Jones and Bodenstine, 2022 ). The mutation mediated by VHL/HIF-1α can up-regulate the expression of glucose transporter 1 (GLUT-1) in ccRCC, and the glycolysis related gene lactate dehydrogenase A (LDHA) also strongly expresses in several tumor cell lines and RCC.…”

Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment

“…Glucose is a vital carbon substrate for generating energy and metabolic intermediates ( 146 ). Cancer cells frequently rely on glycolytic metabolism for maintenance; nonetheless, cellular reprogramming of metabolic processes frequently occurs in developing tumors when blood perfusion is constrained ( 147 ). For instance, circGOT1 functions as an oncogene in ESCC, which promotes aerobic glycolysis through the miR-606/GOT1 axis, acting as an mRNA sponge ( 86 ).…”