MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway

Abstract

Despite favorable responses to initial therapy, SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. 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 that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is has not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3/AKT pathway in a SOX2-dependent manner. Metabolomic profiling revealed that MCAM modulates lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.

RETRACTED: Inhibition of Notch1 reverses EMT and chemoresistance to cisplatin via direct downregulation of MCAM in triple‐negative breast cancer cells

“…A study by Zabouo and colleagues also reported that MCAM expression was a poor prognostic indicator in human breast tumors . In small‐cell lung cancer, it had been reported that MCAM mediated chemoresistance via regulating the PI3K/AKT/SOX2 pathway . Up to now, the interrelationship and possible regulatory effects of Notch and MCAM in breast cancer remain not yet clear.…”

SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma

“…Previous studies have indicated the role of SOX2 on inducing ABCC1 expression, [22][23][24] but no direct evidence confirms this function of SOX2 until now. Here, the induction of SOX2 increased mRNA and protein levels of ABCC1 in the five melanoma cell lines ( Figure 4A,B),…”

Cancer Stem Cell Plasticity – A Deadly Deal

“…heterogeneity) and the ability to switch among them (i.e. plasticity) (Huang, Jolly et al 2015, Mooney, Talebian et al 2017, Tripathi, Fahrmann et al 2017, Jolly, Preca et al 2018, Saha, Kumar et al 2018.…”