CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis

Abstract

Anoikis resistance was a prominent hallmark of cancer metastasis, and lipo-genic characteristics have been identified as another metabolic alteration during tumorigenesis. However, their crosstalk has not been fully elucidated, especially in advanced esophageal squamous cell carcinoma (ESCC). In this study, we showed, for the first time, that the key enzyme carnitine O-palmitoyl transferase 1 (CPT1A), which is involved in fatty acid oxidation (FAO), was markedly upregulated in ESCC cells upon detached culture via a metabolism PCR array. Overexpression of CPT1A was associated with poor survival of ESCC patients and could protect ESCC cells from apoptosis via maintaining redox homeostasis through supply of GSH and NADPH. Mechanistically, detached culture conditions enhanced the expression of the transcription factor ETV4 and suppressed the expression of the ubiquitin enzyme RNF2, which were responsible for the elevated expression of CPT1A at the mRNA and protein levels, respectively. Moreover, genetic or pharmacologic disruption of CPT1A switched off the NADPH supply and therefore prevented the anchorage-independent growth of ESCC cells in vitro and lung metastases of xenografted tumor models in vivo. Collectively, our results provide novel insights into how ESCC cancer cells exploit metabolic switching to form distant metastases and some evidence for the link between anoikis and FAO.