Effects of the HIF-1α and NF-κB loop on epithelial-mesenchymal transition and chemoresistance induced by hypoxia in pancreatic cancer cells

Abstract

Abstract. Hypoxia is a microenvironmental factor which plays a critical role in tumor development and chemoresistance. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical causes of treatment failure and chemoresistance in different types of human cancers. Stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription complex, caused by intratumoral hypoxia, promotes tumor progression and chemoresistance. Previous evidence suggests that hypoxia can also activate nuclear factor-κB (NF-κB), a known mediator of EMT, which is accompanied by reduced expression of epithelial marker E-cadherin and enhanced expression of the mesenchymal markers Vimentin and N-cadherin as well as overexpression of various transcription factors of EMT, such as Snail and Twist. Based on this evidence, the present study aimed to investigate whether downregulation of the p65 subunit of NF-κB or HIF-1α by small interfering RNA (siRNA) may reverse the EMT phenotype and inhibit the proliferation and induce the apoptosis of pancreatic cancer cell lines (PANC-1, BxPC3) under hypoxic conditions in vitro and enhance the efficacy of gemcitabine in the treatment of pancreatic cancer. These results provide molecular evidence showing that the activation of the HIF-1α and NF-κB loop is mechanistically linked with the chemoresistance phenotype (EMT phenotype) of pancreatic cancer cells under hypoxic conditions, suggesting that the inactivation of HIF-1α and NF-κB signaling by novel strategies may be a potential targeted therapeutic approach for overcoming EMT and chemoresistance induced by hypoxia.

The radiosensitising effect of gemcitabine and its main metabolite dFdU under low oxygen conditions is in vitro not dependent on functional HIF-1 protein

“…Suppression of HIF-1α using siRNA resulted in an enhanced efficacy of gemcitabine in the treatment of several pancreatic tumour cell lines [40, 41]. Nevertheless, in line with our results, knockdown of HIF-1α has also been reported to have no effect on the sensitivity of pancreatic PANC-1 cells when treated with gemcitabine under hypoxic conditions [35].…”

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

“…Experimental studies have revealed that the stabilization of HIF-1␣ by hypoxia can directly or indirectly stimulate the expression of several E-box-binding transcription factors known to regulate EMT, including TWIST1, ZEB2, and SNAIL (64,90,121,124), while discrepancies among models suggest context-dependent events. Additionally, under some circumstances, hypoxia may sustain major CSC and EMT-regulatory pathways, such as TGF-␤, nuclear factor-B, and Notch signaling pathways (16,69,96,122,123). Recently, a new concept, that EMT can modulate the antitumor immune response, has emerged.…”

Activity and Expression Pattern of NF-κB/P65 in Peripheral Blood from Hepatocellular Carcinoma Patients - Link to Hypoxia Inducible Factor -1α

“…NF-κB is a critical transcriptional activator of HIF-1α and basal nuclear factor-κB activity is required for HIF-1α protein accumulation under hypoxia (Taylor et al, 2009). Moreover, a hypoxia-dependent transcriptional Hanaa Hibishy Gaballah et al upregulation of hypoxia-inducible factor-1α by nuclear factor-κB was reported in several types of cancer (Yoshida et al, 2013), stimulating epithelial to mesenchymal transition (Cheng et al, 2014), thus promotinralg tumor growth and angiogenesis.…”