Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Abstract

Purpose Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN).This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA damage repair following ionizing radiationtherapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design Expression of survivin in SCCHN patient primary tumor tissues (n=100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo. Results Overexpression of survivin was significantly associated with lymph nodes metastatic status (p=0.025), worse overall survival (OS) and disease free survival (DFS) in patients receiving RT (n=65, OS: p=0.024, DFS: p=0.006) and in all patients with SCCHN (n=100, OS: p=0.002, DFS: p=0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions Survivin is a negative prognostic factor and is involved in DNA damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities.

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…Furthermore, reduction of survivin expression by Brexpiprazole sensitizes glioma cells to osimertinib treatment (33). In addition, suppression of survivin promotes the tumor-killing effect of radiotherapy in prostate cancer (34) and head and neck squamous cell carcinoma (HNSCC) (35,36). In the present study, we found that survivin is highly expressed in OSCC Recent studies showed that the ubiquitin-proteasome pathway induces survivin degradation in a cell cycle-dependent manner (10).…”

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…Similar effect was observed in oral cancer cells where honokiol suppressed JAK2/STAT3 activation and, inhibited IL-6-mediated cell migration [95,183]. Furthermore, another study indicated that honokiol induces apoptosis in human glioblastoma cell line U87 through suppressing the phosphorylation of STAT3 (Tyr705), down-regulating survivin, and upregulating cleaved caspase-3 expression [98].…”

“…The increasing ratio of proapoptotic to antiapoptotic Bcl-2 family proteins (Bax/Bcl-2) will induce the release of cytochrome c and other apoptogenic proteins through the mitochondrial membrane to the cytosol, subsequently leading to the activation of caspase cascade and apoptosis [34]. Furthermore, honokiol downregulated the expression of several other anti-apoptosis mRNA and proteins such as Bcl-xL [13,18,25,64], survivin [67,98], and MCL-1 [18], as well as upregulated other pro-apoptotic proteins such as BAD, BAX, and BAK proteins [18,25].…”

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…Furthermore, reduction of survivin expression by Brexpiprazole sensitizes glioma cells to osimertinib treatment [33]. In addition, suppression of survivin promotes the tumorkilling effect of radiotherapy in prostate cancer [34] and head and neck squamous cell carcinoma (HNSCC) [35,36]. In the present study, we found that survivin is highly expressed in OSCC tumor tissues and cells, depletion of survivin expression by sgRNA blunted the malignant phenotypes in OSCC cells, including in vitro cell proliferation, colony formation, and in vivo tumor development.…”