CAGE Binds to Beclin1, Regulates Autophagic Flux and CAGE-Derived Peptide Confers Sensitivity to Anti-cancer Drugs in Non-small Cell Lung Cancer Cells

Abstract

The objective of this study was to determine the role of CAGE, a cancer/testis antigen, in resistance of non-small cell lung cancers to anti-cancer drugs. Erlotinib-resistant PC-9 cells (PC-9/ER) with EGFR mutations (ex 19 del + T790M of EGFR), showed higher level of autophagic flux than parental sensitive PC-9 cells. Erlotinib and osimertinib increased autophagic flux and induced the binding of CAGE to Beclin1 in PC-9 cells. The inhibition or induction of autophagy regulated the binding of CAGE to Beclin1 and the responses to anti-cancer drugs. CAGE showed binding to HER2 while HER2 was necessary for binding of CAGE to Beclin1. CAGE was responsible for high level of autophagic flux and resistance to anti-cancer drugs in PC-9/ER cells. A peptide corresponding to the DEAD box domain of CAGE, 266AQTGTGKT273, enhanced the sensitivity of PC-9/ER cells to erlotinib and osimertinib, inhibited the binding of CAGE to Beclin1 and regulated autophagic flux in PC-9/ER cells. Mutant CAGE-derived peptide 266AQTGTGAT273 or 266AQTGTGKA273 did not affect autophagic flux or the binding of CAGE to Beclin1. AQTGTGKT peptide showed binding to CAGE, but not to Beclin1. FITC-AQTGTGKT peptide showed co-localization with CAGE. AQTGTGKT peptide decreased tumorigenic potentials of PC-9/ER and H1975 cells, non-small cell lung cancer (NSCLC) cells with EGFR mutation (L885R/T790M), by inhibiting autophagic fluxand inhibiting the binding of CAGE to Beclin1. AQTGTGKT peptide also enhanced the sensitivity of H1975 cells to anti-cancer drugs. AQTGTGKT peptide showed tumor homing potential based on ex vivo homing assays of xenograft of H1975 cells. AQTGTGKT peptide restored expression levels of miR-143-3p and miR-373-5p, decreased autophagic flux and conferred sensitivity to anti-cancer drugs. These results present evidence that combination of anti-cancer drug with CAGE-derived peptide could overcome resistance of non-small cell lung cancers to anti-cancer drugs.

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

“…Hence, it is reasonable to conclude that autophagy plays a protective role against OSI-induced CRC suppression. It has been reported that OSI could induce acquired drug resistance in NSCLC patients 40 , mainly due to a second mutation of EGFR (such as C797 mutation) 41 , or activation of by-pass pro-survival signaling pathways such as MET/ERK, HER2, IRE1α or RAS 41–44 . Our data demonstrate autophagy as an additional drug resistance mechanism for OSI treatment in both NSCLC and CRC, suggesting that combinatorial use of OSI with autophagy inhibitors may benefit their therapeutic efficacy for cancer treatment.…”

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

“…Mersakova et al (2018) and Rong et al (2019) have recently shown that CADM1 is a potential biomarker for cervical cancer. There was a significant difference in the promoter Kan et al, 2014;Lai et al, 2014;Kong et al, 2015;Nikolaidis et al, 2015;Xu et al, 2015Xu et al, , 2018Chen et al, 2016;Liou et al, 2016;Huang et al, 2017;Fang et al, Lee et al, 2006;Yeon et al, 2018 methylation of plasma CADM1 and its D-dimer between healthy individuals and those with cervical cancer. Combining these factors to predict metastasis revealed high specificity (90.5%) and sensitivity (80.4%) (Rong et al, 2019).…”

Effects of miR-373 Inhibition on Glioblastoma Growth by Reducing Limk1 In Vitro

“…Abnormal levels of miRNAs were demonstrated in the process of carcinogenesis or progression, such as lung cancer [ 45 ] and GBM [ 15 , 16 ]. It has been studied that some genes such as miR-373 [ 22 ] or miR-21 [ 21 ] play an important role in above resistance effects of cancer therapy. But there were few studies on whether inhibition on miR-373 may induce above antiresistance effects in GBM treatment and which downstream effector was involved in its process, which need to be confirmed by further experimental data or evidence.…”

“…Therefore, changing the level of above oncogenes or tumor suppressors by using molecular biological methods could provide great assistance to clinical therapy of tumor patients. In addition, some reports showed [ 17 – 19 ] that the resistance of chemo- or radiotherapy on tumor clinical treatment was also related to the effects of miRNAs, such as miR-100 [ 20 ], miR-21 [ 21 ], miR-373 [ 22 , 23 ], but the underlying mechanism was still unclear.…”