Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer

Abstract

Tumor hypoxia has been recognized as a characteristic of the tumor microenvironment and promotes metastasis in a variety of types of cancer. However, in lung cancer, the role of hypoxia-inducible factor 1α (HIF-1α) in modulating the cellular response to the inflammation-related microenvironment remains unclear. In the present study, enhanced expression of HIF-1α accompanied by an increased ROS level was observed in lipopolysaccharide (LPS)-stimulated non-small cell lung cancer (NSCLC) cells. In addition, propofol, a general anesthetic, was found to significantly reduce the LPS-induced upregulation of HIF-1α and ROS in a dose-dependent manner. Further study showed that propofol may antagonize the role of LPS in activating HIF-1α through attenuating the protein stability and nuclear localization of HIF-1α. Moreover, knockdown of HIF-1α attenuated expression of mesenchymal marker, vimentin, but promoted the expression of epidermal marker, E-cadherin, in the LPS-treated NSCLC cells. Notably, LPS-induced epithelial-to-mesenchymal transition (EMT) was notably suppressed by propofol treatment. Consistently, a wound healing assay revealed that propofol abrogated LPS-stimulated migration of NSCLC cells while overexpression of HIF-1α reversed the effects of propofol. Similarly, we investigated the influence of propofol on the invasive capability of NSCLC cells. Western blot and RT-PCR analyses indicated that both knockdown of HIF-1α and treatment of propofol attenuated the LPS-activated expression of MMP2 and MMP9 which are necessary for tumor invasion. However, results from the Transwell assay confirmed that propofol also suppressed cell invasion by decreasing HIF-1α expression in the LPS-treated NSCLC cells. Analysis of clinical specimens demonstrated abnormal expression of HIF-1α in NSCLC tissues and a poor prognosis in patients with elevated HIF-1α expression. Thus, the present study suggests a potential strategy for NSCLC by targeting HIF-1α.

Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

“…LPS serves not only as a physical barrier to keep bacteria from invading the outside environment, but also as a biomarker for the immune system to identify pathogenic bacteria, playing a key role in the inflammatory immune response and endotoxic shock . Endotoxins released by bacteria can affect the proliferation of A549 cells in vitro, and LPS can strongly induce NSCLC cell proliferation in many animal models …”

“…[14][15][16] Endotoxins released by bacteria can affect the proliferation of A549 cells in vitro, and LPS can strongly induce NSCLC cell proliferation in many animal models. [17][18][19] In recent years, with the continuous development of traditional Chinese medicine (TCM), the national investment in TCM research has gradually increased and the anticancer role and underlying mechanisms of TCM have been elucidated to a certain extent. Active ingredients and natural Chinese herbal medicines play an important role in improving immune function, inhibiting cell proliferation and migration, promoting cell apoptosis, alleviating clinical symptoms, alleviating toxicity and the side effects of radiotherapy and chemotherapy, prolonging survival, reducing recurrence, and improving quality of life.…”

The mechanism of propofol in cancer development: An updated review

“…proved that propofol inhibited HIF‐1α protein synthesis which was dependent on the cellular oxygen tension . In lung cancer, propofol decreased HIF‐1α protein stability and nuclear localization induced by lipopolysaccharide . Huang et al.…”

“…46 In lung cancer, propofol decreased HIF-1 protein stability and nuclear localization induced by lipopolysaccharide. 47…”

Propofol prevents IL‐13‐induced epithelial–mesenchymal transition in human colorectal cancer cells

“…Besides, patients with propofol treatment had higher overall 1‐year survival rate than patients with sevoflurane treatment during colon and breast cancer surgery (Enlund et al, ). In addition, propofol was found to suppress cancer‐related inflammation (Yang et al, ). For instance, propfol exerts its anti‐inflammation activity by blocking phosphorylation of nuclear factor‐κB, p38 mitogen‐activated protein kinase pathway (Liu et al, ), and inducing the degradation of TGF‐β1 (Xu et al, ).…”