Thromboxane A2 receptor α promotes tumor growth through an autoregulatory feedback pathway

Abstract

Tobacco smoking can cause a number of cancers. The role of thromboxane synthase (TxAS) in smoking-related cancers is largely unknown. In this study, 37 pairs of tumor and non-tumor lung tissues of non-small-cell lung cancer, 5 lung cancer cell lines, and a mouse tumor model were used to study TxAS and its related molecules. A mouse model of smoking carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK)-induced lung tumor showed an increase in TxAS. Thromboxane A2 receptor (TP) was aberrant in lung cancer tissues of smokers. TxAS and TP were increased in lung tissues of NNK-treated mice. The in vitro studies showed that TPα rather than TPβ promoted tumor growth, and NNK increased TPα. NNK-induced TxAS, which depended on activation of cyclooxygenase-2 (COX-2), ERK and NF-κB, could be inhibited by miR-34b/c. TPα played a positive role in NNK-induced COX-2/ERK/NF-κB activation, leading to the upregulation of TxAS expression and thromboxane A2 (TxA2) synthesis. The newly synthesized TxA2 could further activate TPα, forming an autoregulatory feedback loop for TPα activation. Collectively, NNK promotes lung tumor growth via inducing TxAS and TPα, which constitutes an auto-positive feedback loop to exaggerate the growth. This study suggests that TPα and TxAS are the ideal targets against smoking-related lung cancer.

Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms

“…As expected, several studies showed that TxA 2 antagonist, TxAS inhibitor, or TP antagonist could inhibit cancer cell growth and induce apoptosis by increasing the ROS level, inhibiting the NF-κB pathway, increasing the nuclear p27 level, or blocking ERK/CREB signaling in lung cancer, bladder cancer, and glioblastoma [83,[85][86][87][88][89][90][91].…”

“…More explicitly, NNK activates PI3K/AKT and ERK pathways through TP, phosphates CREB, induces the expressions of PCNA and Bcl-2, and thereby promotes lung cancer cell survival [75]. The mechanism by which NNK induces the expression of TxAS has previously been explored [83], whereby NNK increases the TPα protein level and increases the TxAS transcription via the COX-2/ERK/NF-κB pathway. The increased TxAS synthesized new TxA 2 , and further activated TPα, which formed an autoregulatory feedback loop for TPα activation.…”

Effects of Glycyrrhizin in a Mouse Model of Lung Adenocarcinoma

“…Two lung adenocarcinoma cell lines, A549 and NCI-H23, which have been widely used in cancer research, were detected without any transfection in our previous reports [1,11]. It was found that both TPα and TxAS are abundant in A549 but limited in NCI-H23 cells.…”

“…We stably transfected A549 cells with TPα for the three following reasons. First, TPα is believed to facilitate lung cancer growth, invasion and metastasis [8,9,[11][12][13]. Second, the effects of both glycyrrhizin and cisplatin are related to the TxA2 pathway [1,5,15,18].…”

“…In particular, TxAS and the α isoform of the TxA2 receptor (TPα) can facilitate lung tumor growth and metastasis [10,16], and intriguingly, there is a positive feedback loop between TxAS and TPα in lung tumors [11]. Briefly, following activation of TPα by specific binding with TxA2, several transcription factors, such as nuclear factor (NF)-κB and cyclic adenosine monophosphate response element binding protein (CREB), are subsequently activated to induce expression of TxAS, which is the key enzyme for the biosynthesis of TxA2 [8][9][10][11]17]. In addition to being a tumor promoter, TxA2 possibly can be used as a biomarker for tumor cachexia [6] because TxA2 is believed to be involved in the process of cancer cachexia through inducing the chronic inflammatory process [4].…”