MCAM mediates chemoresistance in small cell lung cancer via the PI3K/AKT/SOX2 signaling pathway
Despite favorable responses to initial therapy, small cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Due to limited accessibility of patient tissues for research purposes, SCLC-patient derived xenografts (PDX) have provided the best opportunity to address this limitation. Here we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines and in chemoresistant PDX compared to matched treatment-naive tumors. MCAM depletion in chemoresistant cells reduced cell proliferation and reduced the IC50 inhibitory concentration of chemotherapeutic drugs in vitro. This MCAM-mediated sensitization to chemotherapy occurred via SOX2-dependent upregulation of mitochondrial 37S ribosomal protein 1/ATP binding cassette subfamily C member 1 (MRP1/ABCC1) and the PI3/AKT pathway. Metabolomic profiling revealed that MCAM modulated lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. Our results suggest that MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.
|ISBN||1538-7445 (Electronic) 0008-5472 (Linking)|
|Authors||Tripathi, S. C.; Fahrmann, J. F.; Celiktas, M.; Aguilar, M.; Marini, K. D.; Jolly, M. K.; Katayama, H.; Wang, H.; Murage, E. N.; Dennison, J. B.; Watkins, D. N.; Levine, H.; Ostrin, E. J.; Taguchi, A.; Hanash, S. M.|
|Responsible Garvan Author||(missing name)|
|Publisher Name||CANCER RESEARCH|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28646020|