RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species

Abstract

Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer and mouse lung tumor tissues. RIP1 expression was remarkably increased in cigarette smoke-exposed mouse lung. In human bronchial epithelial cells (HBECs), RIP1 was significantly induced by cigarette smoke extract or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo(a)pyrene. In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs), including c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The ROS-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced ROS accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production.

Receptor-interacting Protein 1 Increases Chemoresistance by Maintaining Inhibitor of Apoptosis Protein Levels and Reducing Reactive Oxygen Species through a microRNA-146a-mediated Catalase Pathway

“…We found that the synthesis rate of catalase was suppressed substantially, whereas the stability of this ROS scavenging protein was decreased slightly within RIP1 knockdown cells, suggesting a dual regulation for catalase expression. This is distinct from the carcinogen benzo(a)pyrene diolepoxide-induced catalase suppression that mainly occurs through proteasomal degradation in immortalized human bronchial epithelial cells (33). These observations suggest that the regulation of catalase expression is complex and, again, may be cell type-or stimulation-specific.…”

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

“…Catalase expression is regulated through different mechanisms including proteasomal protein degradation and miRNA-mediated protein synthesis suppression (25,(36)(37)(38). We found that miR-551b, which is predicted to target the 3′UTR of catalase mRNA, was increased in AR cells and knockdown of miR-551b strongly rescued catalase expression, suggesting an important mechanism in the upregulation of MUC1 through miR-551b-mediated catalase suppression.…”

“…We found MUC1 mRNA was increased in AR cells, which was associated with ROS accumulation resulting from catalase inhibition. ROS activated MAPKs, including ERK, which stimulates MUC1 transcription (38,45). Thus, it is possible that activation of transcription is involved in increased MUC1 expression in AR cells.…”

“…Catalase expression is regulated at multiple levels including translation regulation by different microRNAs in different cell types (25,(36)(37)(38). Thus, we investigated the potential microRNA-mediated regulation of catalase.…”

Cigarette Smoke Modulates NOD1 Signal Pathway and Human ß Defensins Expression in Human Oral Mucosa

“…Study data of Leuk cells also confirmed that CSE augmented RIP2 expression. A recent study suggested that RIP1 expression remarkably increased in cigarette smokeexposed mouse lung and was significantly induced by CSE in human bronchial epithelial cells [36]. As members of receptor-interacting protein family, RIP1 and RIP2 share many common functions in cell death and cell stress signaling [37].…”