Squamous cell carcinomas (SCC) are amongst the most common cancer types afflicting man. SCC frequently arise from stratified squamous epithelia such as the epidermis or the mucosae of the head and neck. Once an SCC becomes invasive it presents a considerable challenge and advanced metastatic CSCC and HNSCC is frequently incurable resulting in approximately1500 reported deaths per year in Australia (AIHW). The high mortality rate is a direct result of the emergence of drug resistance. Thus, there is a clear and overwhelming need for new therapeutic agents and strategies to improve outcomes and/or to improve the efficacy of existing drugs.
We have previously shown that the transcription factors, E2F1 and E2F7 are overexpressed in human SCC and that the ratio of E2F1 to E2F7 determines cytotoxic response to conventional chemotherapeutics (Cancer Res.,69(5):1800-1808, 2009). Using conditional KO cells and a series of overexpression plasmids and siRNAs we now show that the downstream effector of E2F7-mediated suppression of anthracycline sensitivity is E2F-driven induction of sphingosine kinase-1 transcription with consequent activation of S1P pathways. Extending these findings we now report that a combination of a Sphk1 inhibitor + doxorubicin enhances cytotoxicity in resistant SCC cells in vitro and in vivo. Upon closer examination we found that increased Sphk1:S1P production was due to S1P-driven CRM1-dependent export of E2F7 from the nucleus. The nuclear export of E2F7 resulted in the derepression of the Sphk1 promoter leading to increased E2F1-dependent Sphk1 transcription and subsequent S1P production. Thus, we report on a novel E2F-driven axis that regulates sensitivity of SCC cells to anthracyclines. Given that the E2F:Rb axis is disrupted in most cancers it is possible that this mechanism may be observed in other cancer types.