Curcumin increases crizotinib sensitivity through the inactivation of autophagy via epigenetic modulation of the miR-142-5p/Ulk1 axis in non-small cell lung cancer

Article type: Research Article

Authors: He, Yu-Zheng^{a; 1} | Yu, Shan-Ling^{b; 1} | Li, Xiao-Ning^c | Bai, Xian-Hua^d | Li, Hai-Tao^e | Liu, Yan-Chao^e | Lv, Bao-Lei^f | Zhao, Xiu-Min^g | Wei, Dong^h | Zhang, He-Lin^a | Li, Fan-Nianⁱ | Li, GuoLei^j | Li, Shuai^{e; *}

Affiliations: [a] Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China | [b] Department of Medical Intensive Care Unit, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China | [c] Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China | [d] Department of Medical Imaging, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China | [e] Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China | [f] Department of Thoracic Surgery, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei, China | [g] Department of The Integrated Treatment of Traditional Chinese and Western Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China | [h] Department of Thoracic Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China | [i] Department of Thoracic Surgery, The First Hospital of XingTai, XingTai, Hebei, China | [j] Department of The First Surgery, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, Hebei, China

Correspondence: [*] Corresponding author: Shuai Li, Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei 050000, China. Tel.: +86 15931076803; E-mail: [email protected].

Note: [1] Yu-Zheng He and Shan-Ling Yu are co-first authors.

Abstract: Drug resistance is a critical factor responsible for the recurrence of non-small cell lung cancer (NSCLC). Previous studies suggest that curcumin acts as a chemosensitizer and radiosensitizer in human malignancies, but the underlying mechanism remains elusive. In the present study, we explored how curcumin regulates the expression of miR-142-5p and sensitizes NSCLC cells to crizotinib. We found that miR-142-5p is significantly downregulated in NSCLC tissue samples and cell lines. Curcumin could increase crizotinib cytotoxicity by epigenetically restoring the expression of miR-142-5p. Furthermore, curcumin treatment suppressed the expression of DNA methylation-related enzymes, including DNMT1, DNMT3A, and DNMT3B, in NSCLC cells. In addition, the upregulation of miR-142-5p expression increased crizotinib cytotoxicity and induced apoptosis in tumor cells in a similar manner to that of curcumin. Strikingly, miR-142-5p overexpression suppressed crizotinib-induced autophagy in A549 and H460 cells. Mechanistically, miR-142-5p inhibited autophagy in lung cancer cells by targeting Ulk1. Overexpression of Ulk1 abrogated the miR-142-5p-induced elevation of crizotinib cytotoxicity in A549 and H460 cells. Collectively, our findings demonstrate that curcumin sensitizes NSCLC cells to crizotinib by inactivating autophagy through the regulation of miR-142-5p and its target Ulk1.

Keywords: Non-small cell lung cancer, autophagy, miR-142-5p, curcumin, crizotinib

DOI: 10.3233/CBM-210282

Journal: Cancer Biomarkers, vol. 34, no. 2, pp. 297-307, 2022