Abstract
Here we demonstrated that chemotherapy induced 14-3-3σ expression in tongue cancer (TC) cells and overexpressed 14-3-3σ sensitized TC cells to chemotherapy especially in multidrug resistant TC (MDR-TC) cells. In agreement, 14-3-3σ knockdown enhanced resistance of TC cells to chemotherapy. Mechanically, we found 14-3-3σ physically bound to GSK3β in protein level and the binding inhibited β-catenin signaling. Coincidentally, chemotherapy as well as 14-3-3σ overexpression led to increase of GSK3β protein level. Increased GSK3β protein sensitized TC cells to chemotherapy. Moreover, deregulation of 14-3-3σ/GSK3β/β-catenin axis led to overexpressed ZEB1 in TC cells, especially in MDR-TC cells. As a negative feedback loop, ZEB1 bond to 14-3-3σ promoter to enhance promoter hypermethylation in TC cells. Promoter hypermethylation resulted into the decrease of 14-3-3σ expression. Importantly, a positive correlation was observed between 14-3-3σ and GSK3β protein expression in TC tissues from patients receiving chemotherapy. High levels of 14-3-3σ and GSK3β were associated with better prognosis in TC patients.
Highlights
Squamous cell carcinoma (SCC) of the oral cavity represents the tenth most frequent solid cancer worldwide and tongue cancer (TC) is the most common type of oral cancer
The induction of 14-3-3σ expression in the multidrug resistant TC (MDR-TC) cells Tca8113/PYM established in our previous studies was not so remarkable, accompanied with apoptosis resistance (Figure 1D)
To investigate whether 14-3-3σ expression associated with GSK3β and β-catenin protein levels in chemotherapy, we found PYM or cDDP induced marked increase of GSK3β protein levels in Tca8113, SCC-25 and CAL-27 cell lines (Figure 3B) but not in MDR-TC Tca8113/PYM cells
Summary
Squamous cell carcinoma (SCC) of the oral cavity represents the tenth most frequent solid cancer worldwide and tongue cancer (TC) is the most common type of oral cancer. In United States alone, it has been estimated 12,060 new cases and 2030 deaths from TC in 2011 [1]. The current treatment options for TC include surgery, radiotherapy and chemotherapy. Chemotherapy mostly based on pingyangmycin (PYM) and/or cisplatin (cDDP), plays an important role in TC treatment and brings many benefits including reducing tumor size, inhibiting distant metastasis and prolonging patient survival [2]. In the clinic, many TCs are insensitive to chemotherapy because of the intrinsic and/or acquired drug resistance. Chemo-insensitivity of TCs even correlates with more aggressive cancer behavior and an even worse clinical outcome [3]. There is an urgent need to fully understand the biological and molecular actions in the response of TC cells to chemotherapy, and to identify new therapeutic targets to improve the efficacy of chemotherapy
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