HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue

Abstract

Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT. Experimental Design: Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples from SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-κB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IκBα protein level disrupts extracellular HSP27-induced NF-κB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. Clin Cancer Res; 24(5); 1163–75. ©2017 AACR.

MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

“…These data are supported by a pulmonary inflammation model wherein MK2 knockout mice had significantly lower levels of TNF-α and decreased phosphorylated HSP27 (p-HSP27) and NF-κb pathway signaling [46]. Additionally, Zheng and colleagues [47] showed increased HSP27 and IL-6 in chemoresistant squamous tongue carcinoma cells. This increased HSP27 expression activated NF-κb signaling, and led to increased tumor growth in vivo, and high HSP27 levels were correlated with worse overall survival in human patients [47].…”

Quantitative Immunomorphological Analysis of Heat Shock Proteins in Thyroid Follicular Adenoma and Carcinoma Tissues Reveals Their Potential for Differential Diagnosis and Points to a Role in Carcinogenesis

“…It was observed that an increase of Hsp27 levels is transiently induced at specific stages during development and cell differentiation and occurs concomitantly with the differentiation-associated decrease of cellular proliferation [28,29]. Other studies reported that Hsp27 is augmented in different types of tumors and its levels are directly associated with a more aggressive malignant behavior (cancer cell proliferation, invasiveness, and metastasis) and resistance to chemotherapy [30,31]. Furthermore, Hsp27 mediates endothelial cell mobility, improving angiogenesis [32].…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Squamous cell carcinoma of tongue Induction of multidrug-resistance by hyperactivating NF-κB signal and suppressing mitochondrial caspase signal Reduction of chemoresistance via HSP27 knockdown and its antibody treatment [95] Ovarian cancer Induction of cisplatin resistance by inhibiting p21 via activation of AKT pathway [96] Laryngeal cancer cell Induction of chemoresistance to cisplatin and staurosporin by delaying cell growth and remodeling actin polymerization [97] Pancreatic cancer Induction of chemoresistance to gemcitabine by activation of Snail and ERCC1 and decrease of E-cadherin [98] Lung cancer…”

“…HSP27 enhances multidrug-resistance in squamous cell carcinoma of tongue (SCCT) through hyperactivation of NF-κB. [95]. In ovarian cancer, the increased expression of HSP27 induces cellular resistance against cisplatin therapy by inhibiting p21 transfer from the nucleus [96].…”