Irisin Enhances Doxorubicin-Induced Cell Apoptosis in Pancreatic Cancer by Inhibiting the PI3K/AKT/NF-κB Pathway

Abstract

Background Irisin, a myokine released from skeletal muscle following exercise, has been shown to affect the proliferation of some cancer cells and chemosensitivity of anticancer drugs like doxorubicin (DOX). However, the effects of irisin on chemosensitivity in pancreatic cancer (PC) cells have not been studied. Material/Methods In this study, the effects of irisin co-treatment with DOX or gemcitabine (GEM) on MIA PaCa-2, BxPC-3 PC cells, and H9c2 cardiomyocytes were investigated. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, flow cytometry, and TUNEL (TdT-mediated dUTP nick-end labeling) assays were conducted to evaluate cytotoxicity induced by DOX or GEM. Fluorescence microscopy and flow cytometry experiments were performed to assess the intracellular accumulation of DOX. Cellular levels of apoptosis-related protein expression and protein phosphorylation were determined by Western blot analyses. Results The results showed that irisin can increase the chemosensitivity of PC cells to DOX or GEM. The analyses of apoptosis indicated that irisin enhances DOX-induced cellular apoptosis by increasing the expression of cleaved PARP (poly ADP-ribose polymerase) and cleaved caspase-3, and reducing the expression of B cell lymphoma/lewkmia-2 (BCL-2) and B cell lymphoma-extra large (BCL-xL) in PC cells but not in H9c2 cells. Irisin attenuated serine/threonine kinase AKT (protein kinase B/PKB) phosphorylation and inhibited the activation of nuclear factor κB (NF-κB) signaling in PC cells. Conclusions Irisin can potentiate the cytotoxicity of doxorubicin in PC cells without increasing cardiotoxicity, possibly through inactivating the PI3K/AKT/NF-κB signaling pathway.

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin

“…In addition, irisin has been shown to suppress pancreatic cancer cell growth and proliferation (Liu et al, 2018), and to enhance doxorubicin-induced pancreatic cancer cell apoptosis through the upregulation of caspase-3 expression and the reduction of anti-apoptotic B-cell lymphoma 2 (Bcl-2) and Bcl-xL expression (Liu et al, 2019). Irisin potentiated the effects of chemotherapeutic agents in pancreatic cancer cells via suppression of the PI3K/AKT/NF-KB signaling pathway (Liu et al, 2019; Figure 4).…”

“…Moreover, irisin was found to not only increase proliferation and invasion of HepG2 cells, but also to decrease doxorubicin-induced HepG2 cell apoptosis, effects that occurred via the PI3K/AKT pathway (Shi et al, 2017; Figure 4). Although both the anti-and pro-tumor effects of irisin seem to involve the PI3K/AKT pathway, the underlying mechanism that might explain these discrepancies remains unknown (Moon and Mantzoros, 2014;Gannon et al, 2015;Shao et al, 2017;Shi et al, 2017;Liu et al, 2019). Further studies are required to validate the differential effects of irisin on different cancers.…”

Deoxyelephantopin induces apoptosis via oxidative stress and enhances gemcitabine sensitivity in vitro and in vivo through targeting the NF-κB signaling pathway in pancreatic cancer

“…Furthermore, multiple studies have confirmed that NF-κB is in a continuous abnormal activation state in pancreatic cancer cell lines, animal models of cancer and even human tumor specimens [27]. NF-κB activation plays a regulatory role in gene expression, leading to malignant biological phenotypes and chemoresistance [28][29][30]. In contrast, suppressing abnormal activation of NF-κB significantly enhances the antitumor effect of GEM in pancreatic cancer [29,30].…”

“…NF-κB activation plays a regulatory role in gene expression, leading to malignant biological phenotypes and chemoresistance [28][29][30]. In contrast, suppressing abnormal activation of NF-κB significantly enhances the antitumor effect of GEM in pancreatic cancer [29,30]. In summary, to make progress in pancreatic cancer treatment, the exploration of novel agents that could effectively block the activation of NF-κB is urgently needed.…”

<p>Huaier Restrains Cholangiocarcinoma Progression in vitro and in vivo Through Modulating lncRNA TP73-AS1 and Inducing Oxidative Stress</p>

“…Among them, more and more traditional Chinese medicine (TCM) which have anti-tumor properties have been discovered and investigated. [9][10][11][12] Huaier, the fruiting body of Trametes robiniophila Murr, is a kind of light-tawny mushroom parasitic on the boles of locust trees. 13 According to the records of TCM, Huaier is usually used as an anti-inflammatory.…”