Dual Targeting of the p38 MAPK-HO-1 Axis and cIAP1/XIAP by Demethoxycurcumin Triggers Caspase-Mediated Apoptotic Cell Death in Oral Squamous Cell Carcinoma Cells.

Ming-Hsien Chien,Wei-Jiunn Lee,Yi-Chieh Yang,Chia-Chi Ku,Shun-Fa Yang,Wei-En Yang,Chiao-Wen Lin,Meng-Ying Tsai

doi:10.3390/cancers12030703

Abstract

Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects and underlying mechanisms of DMC against OSCC. We found that DMC suppressed cell proliferation via simultaneously inducing G2/M-phase arrest and cell apoptosis. Mechanistic investigations found that the downregulation of cellular IAP 1 (cIAP1)/X-chromosome-linked IAP (XIAP) and upregulation of heme oxygenase-1 (HO-1) were critical for DMC-induced caspase-8/-9/-3 activation and apoptotic cell death. Moreover, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK)1/2 were activated by DMC treatment in OSCC cells, and only the inhibition of p38 MAPK significantly abolished DMC-induced HO-1 expression and caspase-8/-9/-3 activation. The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO-1 and low cIAP1 had the most favorable prognoses. Furthermore, a combinatorial treatment of DMC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, significantly enhanced the inhibitory effect of gefitinib on the proliferation of OSCC cells. Overall, the current study supported a role for DCM as part of a therapeutic approach for OSCC through suppressing IAPs and activating the p38-HO-1 axis.

Highlights

Oral squamous cell carcinoma (OSCC) accounts for 90% of head and neck cancers located in the oral cavity and is the sixth leading cancer by incidence worldwide [1]
To confirm apoptosis by cell observations, HSC-3 and SCC-9 cells were treated with 25 μM DMC for h, stained with Hoechst 33342, morphological observations, HSC-3 and SCC-9 cells were treated with μM DMC for 24 h, stained and observed by fluorescence microscopy
An increase in the sub-G1 peak, which is an characteristic feature of cell apoptosis, was induced by DMC, suggesting that G2 /M arrest is an underlying mechanism inhibiting the growth of DMC-treated oral squamous cell carcinoma (OSCC) cells, which might further turn on an apoptotic program

Summary

Introduction

Oral squamous cell carcinoma (OSCC) accounts for 90% of head and neck cancers located in the oral cavity and is the sixth leading cancer by incidence worldwide [1]. Due to the unsatisfactory results of these standard treatments for OSCC, identifying new agents is crucial. Solid malignant tumors, such as OSCC, have the potential for rapid and unlimited growth due to resistance to apoptosis [3]. The overexpression of an family of antiapoptotic proteins termed inhibitor of apoptosis (IAP) proteins, including cellular IAP 1 and 2 (cIAP1 and cIAP2, encoded by BIRC2 and BIRC3), X-chromosome-linked IAP (XIAP, encoded by BIRC4), and survivin was reported to confer resistance to radiation therapy and chemotherapy and cause poor prognoses of patients with head and neck cancers, including OSCC [4,5,6,7].

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