Abstract
The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy.
Highlights
Despite recent improvement in treatment of head and neck squamous cell carcinoma (HNSCC), the increase in overall survival has been minimal, with treatment failure and disease recurrence continuing to be a problem in many patients [1]
To investigate whether a similar CD44v-dependent mechanism is operative in HNSCC cells, we examined the effects of cisplatin, whose cytotoxicity is mediated, in part, by reactive oxygen species (ROS) [23], on the viability of 4 HNSCC cell lines that differ in CD44v expression status (Fig. 2A and Supplementary Fig. S1A)
To examine whether tumor cell differentiation might affect the response to sulfasalazine, we investigated the effects of 9cis-retinoic acid, which promotes the differentiation of a subset of HNSCC cells including HSC-2 cells [28]
Summary
Despite recent improvement in treatment of head and neck squamous cell carcinoma (HNSCC), the increase in overall survival has been minimal, with treatment failure and disease recurrence continuing to be a problem in many patients [1]. Tumor formation, relapse, and metastasis are thought to be driven by a subpopulation of cancer cells. These stem-like cancer cells are generally more resistant to cancer treatments, including chemo- and radiotherapy, compared with non–stem-like cancer cells [2,3,4]. Possess the properties of stem-like cancer cells [5, 6]. The selective killing of CD44-expressing stem-like cancer cells might be required for effective therapy in patients with HNSCCs
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