CAGE与Beclin1结合，调节自噬通量，且CAGE衍生肽赋予非小细胞肺癌细胞对抗癌药物的敏感性。
CAGE Binds to Beclin1, Regulates Autophagic Flux and CAGE-Derived Peptide Confers Sensitivity to Anti-cancer Drugs in Non-small Cell Lung Cancer Cells.
作者信息
Yeon Minjeong, Byun Jaewhan, Kim Hyuna, Kim Misun, Jung Hyun Suk, Jeon Doyong, Kim Youngmi, Jeoung Dooil
机构信息
Department of Biochemistry, Kangwon National University, Chunchon, South Korea.
L-Base Company, Seoul, South Korea.
出版信息
Front Oncol. 2018 Dec 10;8:599. doi: 10.3389/fonc.2018.00599. eCollection 2018.
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, AQTGTGKT, 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 AQTGTGAT or AQTGTGKA 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 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.
本研究的目的是确定癌症/睾丸抗原CAGE在非小细胞肺癌对抗癌药物耐药性中的作用。具有EGFR突变（EGFR外显子19缺失+T790M）的厄洛替尼耐药PC-9细胞（PC-9/ER）比亲代敏感PC-9细胞表现出更高水平的自噬通量。厄洛替尼和奥希替尼增加了PC-9细胞中的自噬通量，并诱导CAGE与Beclin1结合。自噬的抑制或诱导调节了CAGE与Beclin1的结合以及对抗癌药物的反应。CAGE显示与HER2结合，而HER2是CAGE与Beclin1结合所必需的。CAGE导致PC-9/ER细胞中高水平的自噬通量和对抗癌药物的耐药性。一种与CAGE的DEAD框结构域对应的肽AQTGTGKT增强了PC-9/ER细胞对厄洛替尼和奥希替尼的敏感性，抑制了CAGE与Beclin1的结合，并调节了PC-9/ER细胞中的自噬通量。突变的CAGE衍生肽AQTGTGAT或AQTGTGKA不影响自噬通量或CAGE与Beclin1的结合。AQTGTGKT肽显示与CAGE结合，但不与Beclin1结合。FITC-AQTGTGKT肽与CAGE共定位。AQTGTGKT肽通过抑制自噬通量和抑制CAGE与Beclin1的结合，降低了PC-9/ER和H1975细胞（具有EGFR突变（L885R/T790M）的非小细胞肺癌（NSCLC）细胞）的致瘤潜力。AQTGTGKT肽还增强了H1975细胞对抗癌药物的敏感性。基于H1975细胞异种移植的归巢试验，AQTGTGKT肽显示出肿瘤归巢潜力。AQTGTGKT肽恢复了miR-143-3p和miR-373-5p的表达水平，降低了自噬通量，并赋予了对抗癌药物的敏感性。这些结果表明，抗癌药物与CAGE衍生肽联合使用可以克服非小细胞肺癌对抗癌药物的耐药性。
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