Abstract
Simple SummaryTherapy resistance in head and neck squamous cell carcinoma (HNSCC) patients is the main obstacle to achieve more effective treatments that improve survival and quality of life of these patients. Therefore, it is of vital importance to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. We conducted a comparative proteomic study involving cisplatin-resistant cells and cancer stem cells with the aim of identifying proteins potentially implicated in the acquisition of cisplatin resistance. Through this study, we identified for the first time tetraspanin-1 (TSPAN1) as an important protein involved in the development, progression and chemoresistance of HNSCC tumors.Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial–mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a aggressive cancer type since approximately 60% of patients have locally advanced disease upon diagnosis and approximately half of affected individuals do not survive more than five years after diagnosis [1]
We identified tetraspanin-1 (TSPAN1) as one of the most significantly upregulated proteins in CCL-138-R cells and cancer stem cells (CSCs) compared to parental CCL-138 cells
In order to identify proteins that might potentially have a relevant role in cancer chemoresistance, a proteomic analysis was performed to compare the proteins expressed in parental CCL-138 cells vs
Summary
Head and neck squamous cell carcinoma (HNSCC) is a aggressive cancer type since approximately 60% of patients have locally advanced disease upon diagnosis and approximately half of affected individuals do not survive more than five years after diagnosis [1]. Current chemotherapeutic options for HNSCC patients comprise chemotherapy, based mainly on cisplatin (CDDP) and 5-fluorouracil, taxanes or cetuximab in certain metastatic tumors [2,3]. Resistance to stress, ultra-violet (UV) light, and chemotherapy or radiation treatment can be intrinsic or acquired. There is a general belief that resistance appears through natural selection of pre-existing mutant clones during stress. A novel type of resistance appears throughout the administration of chemotherapeutic agents, which seems to be related to treatment failure in cancer patients. The acquisition of resistance to one drug, usually favors the acquisition of resistance to other unrelated compounds, suggesting that the mechanisms of therapy resistance developed by cancer cells seem to follow a universal pattern against a wide variety of drugs [5,6]
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