Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

“…Reactive oxygen species (ROS) are active compounds that generally contain oxygen and result from aerobic metabolism [4]. In the past, ROS were generally thought to be merely toxic by-products of aerobic metabolism.…”

CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

“…Previous researches have indicated that JNK/c-Jun signaling pathway that belongs to mitogen-activated protein kinase (MAPK) pathway, has vital function in regulating autophagic cell death. For example, Bai, Y. et al have reported that PDIA6 knockdown suppressed NSCLC cell proliferation and increased cisplatininduced autophagic cell death via interacting with MAP4K1 to activate the JNK/c-Jun signaling pathway [43]; Hu, L. et al have proved that SNX-2112, the Hsp90 inhibitor, enhanced TRAIL-induced apoptosis and autophagy of cervical cancer cells through activating the ROS-regulated JNK-p53-autophagy-DR5 pathway [32]; Zhu, Q. et al indicated that irinotecan (IRI) stimulated the reactive oxygen species (ROS)related JNK-and p38-MAPK signaling pathways to increase autophagy-dependent apoptosis and inhibit growth of gastric cancer cells [44]. Therefore, the active status of the JNK/c-Jun signaling pathway was detected under CASK knockdown condition in the present study.…”

“…Increasing studies have con rmed that JNK pathway activation plays a pivotal role in regulating autophagy, and is closely related with chemoresistance and tumor progression [32][33][34]. To further investigate the mechanism of CASK knockdown-induced autophagy, the effect of CASK knockdown on the JNK pathway was detected.…”

<p>Antitumorigenic Effect of Hsp90 Inhibitor SNX-2112 on Tongue Squamous Cell Carcinoma is Enhanced by Low-Intensity Ultrasound</p>

“…Hsp90 affects the expression and function of more than 100 client proteins, such as Akt, Raf-1, Cdk4, MMP2, and VEGFR2, which regulate cancer cell proliferation, invasion and angiogenesis. 22 The Hsp90 inhibitor, SNX-2112, has been shown to exert antitumor effects on a variety of tumors. However, therapeutic doses of SNX-2112 can also exert significant off-target toxicity.…”