title: Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells.
abstract: In recent years, studies of cancer development and recurrence have been influenced by the cancer stem cells (CSCs)/cancer-initiating cells (CICs) hypothesis. According to this, cancer is sustained by highly positioned, chemoresistant cells with extensive capacity of self renewal, which are responsible for disease relapse after chemotherapy. Growth of cancer cells as three-dimensional non-adherent spheroids is regarded as a useful methodology to enrich for cells endowed with CSC-like features. We have recently reported that cell cultures derived from malignant pleural effusions (MPEs) of patients affected by adenocarcinoma of the lung are able to efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we were able to identify a set of genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. One of the most strongly upregulated gene was stearoyl-CoA desaturase (SCD1), the main enzyme responsible for the conversion of saturated into monounsaturated fatty acids. In the present study, we show both by RNA interference and through the use of a small molecule inhibitor that SCD1 is required for lung cancer spheroids propagation both in stable cell lines and in MPE-derived primary tumor cultures. Morphological examination and image analysis of the tumor spheroids formed in the presence of SCD1 inhibitors showed a different pattern of growth characterized by irregular cell aggregates. Electron microscopy revealed that the treated spheroids displayed several features of cellular damage and immunofluorescence analysis on optical serial sections showed apoptotic cells positive for the M30 marker, most of them positive also for the stemness marker ALDH1A1, thus suggesting that the SCD1 inhibitor is selectively killing cells with stem-like properties. Furthermore, SCD1-inhibited lung cancer cells were strongly impaired in their in vivo tumorigenicity and ALDH1A1 expression. These results suggest that SCD1 is a critical target in lung cancer tumor-initiating cells.
authors: 1] Department of Clinical and Molecular Medicine, Sapienza University of Rome, Italy [2] Laboratory of Research and Diagnostics, Department of Surgery 'P.Valdoni', Sapienza University of Rome.
authors: A
authors: A
authors: Noto
authors: S
authors: S
authors: Raffa
authors: C
authors: C
authors: De Vitis
authors: G
authors: G
authors: Roscilli
authors: D
authors: D
authors: Malpicci
authors: P
authors: P
authors: Coluccia
authors: A
authors: A
authors: Di Napoli
authors: A
authors: A
authors: Ricci
authors: M R
authors: MR
authors: Giovagnoli
authors: L
authors: L
authors: Aurisicchio
authors: M R
authors: MR
authors: Torrisi
authors: G
authors: 0000000328518605
authors: G
authors: Ciliberto
authors: R
authors: R
authors: Mancini
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D023102:Anoikis / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*; D016066:Pleural Effusion, Malignant / Q000378:metabolism / Q000473:pathology; D050697:Retinal Dehydrogenase; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
chemical_list: C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase