Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Abstract

Abstract. Although comprehensive strategies in the treatment of colorectal cancer have been developed for a number of years, the five-year survival rate of metastatic colon cancer remains less than 10%. Oxaliplatin, a commonly used chemotherapeutic agent for metastatic colon cancer, improves the response rate of patients and prolongs patients' progression-free survival. However, the generation of resistance limits the clinical application of oxaliplatin, and the mechanisms of this remain unclear. The present study mainly investigated the effect of the gap junction (GJ) composed of connexin43 (Cx43) on oxaliplatin cytotoxicity in colon cancer cells. Three different methods with distinct mechanisms were used to change the function of Cx43 GJs, including cell culture at different densities, pretreatment with a specific inhibitor or enhancer, and special gene knockdown, to observe the cytotoxicity of oxaliplatin and the level of reactive oxygen species (ROS) mediated by Cx43 GJs. The results revealed that the cytotoxicity of oxaliplatin and the level of ROS were decreased with the downregulation of Cx43 GJ function, but exacerbated with the upregulation of Cx43 GJ function. Moreover, ROS scavenging with N-acetyl-L-cysteine and apocynin decreased the cytotoxicity of oxaliplatin. We concluded that the loss of GJ composed of Cx43 contributed to the resistance of oxaliplatin in colon cancer cells, and the mechanism was associated with intracellular ROS alternation. IntroductionColorectal cancer (CRC) is considered to be one of the most frequent causes of cancer-related morbidity and mortality worldwide (1,2). Although comprehensive strategies in the treatment of CRC have been developed for a number of years, the five-year survival rate of metastatic colon cancer is only 10% (3). In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival. Nevertheless, more than 40% of patients still develop significant resistance (3,4). Therefore, how to overcome resistance to oxaliplatin is a key scientific problem to be solved in the treatment of metastatic colon cancers.Connexins are integral membrane proteins, six of which make up a hemi-channel. Two hemi-channels in neighboring cells dock together to form an integral gap junction (GJ). The GJ enables cells to exchange ions and small molecules (with a molecule weight less than 1 kDa) directly, including calcium, glutathione, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Molecules transferred through the GJ are essential for numerous physiological and pathological events (5,6). The connexin gene family constitutes 21 isoforms, the most significant of which is Cx43 (6). The loss of Cx43 is extremely common in the development of cancers and is even involved in advanced stages of tumor progression. The deficiency of Cx43 also contributes to the resistance of chemotherapeutic agents (7). It has been...

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