SCD1 is required for EGFR-targeting cancer therapy of lung cancer via re-activation of EGFR/PI3K/AKT signals
Authors: Jun Huang
Shenghua Fang
Liyan Huang
Ping He
Jiaxi He
Hui Pan
Xingxing Fan
Wei Du
Kelin She
Journal: Cancer Cell International (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: AKT; EGFR; EMT; Lung cancer; SCD1.
Affiliations: 1Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Research Institute of Respiratory Disease, China Key Laboratory of Respiratory Disease, National Center for Clinical Trials on Respiratory Diseases, No. 151 Yanjiangxi Road, Guangzhou, Guangdong 510120 China., 3Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China., 4Department of Thoracic Surgery, Dongguan People's Hospital, Dongguan, Guangdong China., State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, SAR China., 6Department of Pathology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Abstract:  Background: Cancer cells are characterized by aberrant activation of lipid biosynthesis, producing saturated fatty acids and monounsaturated fatty acids via stearoyl-CoA desaturases (SCD) for regulating metabolic and signaling platforms. SCD1 overexpression functions as an oncogene in lung cancer and predicts a poor clinical outcome. This study aimed to investigate the role of SCD1 inhibition by EGFR inhibitor (Gefitinib)-based anti-tumor therapy of lung cancer both in vitro and in vivo. Methods: CCK-8 assay was performed to determine cell viability. The SCD1 mRNA level was detected by qPCR. The protein levels were assessed by Western blotting. E-cadherin and N-cadherin levels were determined by immunofluorescence. Apoptosis detection was conducted by flow cytometry. Cell migration or invasion was evaluated by transwell assay. The tumor sizes and tumor volumes were calculated in nude mice by subcutaneous injection of A549 cells transfected with vector of pcDNA3.1-SCD1 or negative control. Expression of Ki-67 was detected by immunohistochemistry. Result: SCD1 up-regulated expression was observed in lung cancer cell lines. Cells with overexpressed SCD1 had high IC50 values for Gefitinib in A549 and H1573 cell lines. Overexpression of SCD1 inhibited Gefitinib-induced apoptosis, decreased cell vitality and impaired ability of migration and invasion, while these effects were counteracted by A939572. Mechanistically, SCD1 promoted the activation of proliferation and metastasis-related EGFR/PI3K/AKT signaling, and up-regulated epithelial to mesenchymal transition (EMT) phenotype in the two cell lines, which was restored by SCD1 inhibition. Furthermore, in spite of EGFR inhibition, overexpression of SCD1 in vivo significantly promoted tumor growth by activating EGFR/PI3K/AKT signaling in tumor tissues, but A939572 treatment restricted SCD1-induced tumor progression and inhibited EMT phenotype of cancer cells in vivo. Conclusion: These findings indicated that inhibition of oncogene SCD1 is required for targeting EGFR therapy in lung cancer. 

Retracted: No

PubPeer comments:
 Fig 2.  the total apoptosis of A549 (c) and H1573 cells (d) was also determined by flow cytometry . ![file] The A549 and H1573 versions of GEFI+SCD1+A939572 are the same. This could be an error, but how did the two panels end up with different quadrant percentages? Perhaps of greater concern is the coexistence within many panels of two different sizes of dots, as if two different distributions had been superimposed. What flow-cytometry plotting software does that? What software results in a scatter of points outside the box? ![file] Here, two panels share a region of smaller dots. How did this happen? ![file] ,