The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth

• Published in: Cell death & disease Vol. 13; no. 6; p. 569
• Main Authors: Cui, Zihan, Mu, Chuanyong, Wu, Zhichao, Pan, Shu, Cheng, Zewen, Zhang, Zhi-qing, Zhao, Jun, Xu, Chun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.06.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/44; 13/95; 14/19; 14/34; 14/63; 692/699/67/1059/602; 692/699/67/1612/1350; AKT protein; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - genetics; Cell Biology; Cell Culture; Cell cycle; Cell growth; Cell migration; Cell proliferation; Epithelial cells; Genomes; Heat-Shock Proteins - metabolism; Humans; Immunology; Inositol; Inositol - metabolism; Life Sciences; Lung cancer; Lung Neoplasms - genetics; Mice; Mice, Nude; Non-small cell lung carcinoma; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering; Small cell lung carcinoma; Sodium - metabolism; Symporters - genetics; Symporters - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05017-y

Identification of novel molecular signaling targets for non-small cell lung cancer (NSCLC) is important. The present study examined expression, functions and possible underlying mechanisms of the sodium/myo-inositol co-transporter SLC5A3 in NSCLC. The Cancer Genome Atlas (TCGA) database and local NSCLC tissue results demonstrated that SLC5A3 expression in NSCLC tissues (including patient-derived primary NSCLC cells) was significantly higher than that in normal lung tissues and lung epithelial cells. In primary NSCLC cells and immortalized lines, SLC5A3 depletion, using small hairpin RNA (shRNA) and CRSIRP/Cas9 methods, robustly impeded cell proliferation and migration, simultaneously provoking cell cycle arrest and apoptosis. Conversely, ectopic overexpression of SLC5A3 further enhanced proliferation and migration in primary NSCLC cells. The intracellular myo-inositol contents and Akt-mTOR activation were largely inhibited by SLC5A3 silencing or knockout (KO), but were augmented following SLC5A3 overexpression in primary NSCLC cells. Significantly, SLC5A3 KO-induced anti-NSCLC cell activity was largely ameliorated by exogenously adding myo-inositol or by a constitutively-active Akt construct. By employing the patient-derived xenograft (PDX) model, we found that the growth of subcutaneous NSCLC xenografts in nude mice was largely inhibited by intratumoral injection SLC5A3 shRNA adeno-associated virus (AAV). SLC5A3 silencing, myo-inositol depletion, Akt-mTOR inactivation and apoptosis induction were detected in SLC5A3 shRNA virus-injected NSCLC xenograft tissues. Together, elevated SLC5A3 promotes NSCLC cell growth possibly by maintaining myo-inositol contents and promoting Akt-mTOR activation.