Peroxiporins Are Induced upon Oxidative Stress Insult and Are Associated with Oxidative Stress Resistance in Colon Cancer Cell Lines

Abstract

Oxidative stress can induce genetic instability and change cellular processes, resulting in colorectal cancer. Additionally, adaptation of oxidative defense causes therapy resistance, a major obstacle in successful cancer treatment. Peroxiporins are aquaporin membrane channels that facilitate H2O2 membrane permeation, crucial for regulating cell proliferation and antioxidative defense. Here, we investigated four colon cancer cell lines (Caco-2, HT-29, SW620, and HCT 116) for their sensitivity to H2O2, cellular antioxidative status, and ROS intracellular accumulation after H2O2 treatment. The expression of peroxiporins AQP1, AQP3, and AQP5 and levels of NRF2, the antioxidant transcription factor, and PPARγ, a transcription factor that regulates lipid metabolism, were evaluated before and after oxidative insult. Of the four tested cell lines, HT-29 was the most resistant and showed the highest expression of all tested peroxiporins and the lowest levels of intracellular ROS, without differences in GSH levels, catalase activity, nor NF2 and PPARγ levels. Caco-2 shows high expression of AQP3 and similar resistance as HT-29. These results imply that oxidative stress resistance can be obtained by several mechanisms other than the antioxidant defense system. Regulation of intracellular ROS through modulation of peroxiporin expression may represent an additional strategy to target the therapy resistance of cancer cells.

Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors

“…AQP1 expression levels in human and mouse cardiac myocytes correlated with disease severity in hypertrophic hearts; located in cardiac plasma membrane, AQP1-mediated influx of extracellular H 2 O 2 through the intrasubunit water pore resulted in activation of oxidant-sensitive kinases, driving hypertrophic responses that were counteracted by the AQP1 water pore blocker bacopaside II [ 28 ]. Higher levels of expression of peroxiporins AQP1, AQP3 and AQP5 in colon cancer cell lines correlated with better protection from oxidative insults, even when the background activity of antioxidant defense system components remained unchanged [ 92 ]. Human AQP5 was shown to be a highly efficient peroxiporin, characterized in transformed yeast cells exposed to oxidative stress, and in human pancreatic cancer cells [ 93 ].…”

Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway

“…And in this study, we further explored the downstream mechanism. Nrf2 is an factor involved in the modulation of cellular oxidation-reduction balance ( Čipak Gašparović et al, 2021 ). Nrf2 participates in the expression and maturation of various anti-oxidative proteins to maintain the homeostasis of oxidation and reduction ( Ying et al, 2018 ).…”

Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer

“…Since some members of the AQP family facilitate the diffusion of H 2 O 2 , they are also named peroxiporins [ 154 , 155 , 156 , 157 ] and their function has been related to both volume regulation and ROS elimination [ 96 ]. The regulation of H 2 O 2 permeation can also contribute to a resistant phenotype of tumors and peroxiporin activity could modify the cellular antioxidative defense system, thereby contributing to oxidative stress resistance [ 158 ]. AQP1, AQP3, AQP5, AQP8, AQP9, and AQP11 expression was reported in human tumors, and in some cases correlated with tumor grade, opening new diagnostic and therapeutic opportunities [ 56 , 101 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ].…”