KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

Abstract

Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10–20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.

Chk1/2 Inhibition Overcomes the Cisplatin Resistance of Head and Neck Cancer Cells Secondary to the Loss of Functional p53

“…It has been shown in a variety of cell types that the cytotoxic effect of cisplatin is due to activation of p53 and induction of apoptosis (15, 21-23). Previous studies with HNSCC cells have also reported a similar finding (2, 4, 24-26). However, the cisplatin doses used in all of these studies were 10-50 folds higher than the clinically achievable dose of cisplatin.…”

“…Cisplatin, which forms the basis of chemotherapy regimens used for HNSCC treatment, is not effective as a single agent in many patients. Multiple studies have attributed resistance of tumors to cisplatin to reduced drug uptake, increased drug detoxification process, enhanced DNA repair, and suppressed apoptotic response of resistant cells; while others have sought to link the cisplatin responses in HNSCC to the expression levels of certain biomolecules (4, 19, 21, 22, 41). TP53, the tumor suppressor gene, is one such biomolecule found to be mutated in about 60-80% of HPV negative HNSCC specimens (6, 42).…”

“…Surgery and radiation therapy have long been standard treatment regimens for HNSCC, but increasingly chemotherapy is being added as an adjuvant to treat patients with advanced disease. Despite the widespread use of cisplatin in HNSCC, only a subset of patients respond favorably, while a significant number have treatment resistance tumors (2-4). A clear absence of reliable markers predicting cisplatin response has been a major hindrance towards making therapeutic advances in HNSCC (5).…”

LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump

“…Protein extraction and western blotting Assays were performed as described previously by Jiffar et al 39 The antibodies are listed in Supplementary Table 7.…”

Delineating metabolic signatures of head and neck squamous cell carcinoma: Phospholipase A2, a potential therapeutic target

“…In addition, the identification of potential molecular biomarkers of HNSCC could be clinically useful for predicting prognosis and therapeutic efficacy, and also in the development of targeted therapies. To better understand tumor metabolism of HNSCC, most studies have been carried out on HNSCC cells that have been cultured in vitro (Schmitz and Machiels, 2010, Sandulache et al, 2011, Jiffar et al, 2011), and tumor tissues obtained from in vivo conditions (Karahatay et al, 2007, Ziebart et al, 2011). Biomarkers associated with HNSCC that have been identified from tissues or serum/plasma, revealed considerable alterations in protein expression.…”