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

Ana Čipak Gašparović,Monika Mlinarić,Claudia Rodrigues,Lidija Milković,Graça Soveral

doi:10.3390/antiox10111856

Ana Čipak Gašparović, Monika Mlinarić + Show 3 more

Open Access

https://doi.org/10.3390/antiox10111856

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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.

Highlights

The analysis of colorectal cancer (CRC) cases in 40 European countries in 2018 revealedCRC as the second most common cancer diagnosed for women and the third for men [1].The genes known to be involved in CRC development include APC, RAS, BRAF, ERBB2(HER2), as well as MMR status [2]
AQP1, AQP3, and AQP5 were found to be correlated with lymph node metastases in colon cancer patients [25]. The expression of these aquaporins was increased in cancer tissues [26,27], and the inhibition of AQP3 permeability reduced tumor progression in a murine colon cancer model [28]. Taken that these three aquaporins channel H2 O2, our aim was to investigate whether they support tumor growth through regulation of cellular reactive oxygen species (ROS) and antioxidative defense
To study the role of aquaporins in colon cancer cell lines, first, we tested the sensitivity of four colon cancer cell lines to hydrogen peroxide (Figure 1)

Summary

Introduction

(HER2), as well as MMR (mismatch repair) status [2] Some of these genes are used to monitor patients’ status and to define a strategy for cancer treatment [2]. Genetic instability, as one of the hallmarks of cancer, introduces additional mutations, thereby destabilizing normal transcription patterns and transcription regulation. These events support tumor growth, progression, and therapy resistance [3]. An imbalance of the cellular redox status toward oxidation, increases reactive oxygen species (ROS), which regulate cellular processes. When summed, these events boost cancer growth and therapy resistance. To counteract some of the negative consequences of oxidative stress, cells increase their antioxidative defense, especially via the nuclear factor erythroid 2 [NF-E2]-related factor

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