和厚朴酚（honokiol）是从荷花玉兰（俗称洋玉兰、广玉兰、大花木兰）提纯的天然酚类化合物，既往研究结果表明可抑制乳腺肿瘤形成。癌细胞通过自噬作用可逃避抗癌治疗，许多耐药相关分子信号传导通路都可诱导自噬作用。不过，和厚朴酚对乳腺癌细胞自噬作用的具体机制尚不明确。
2020年9月6日，英国《自然》旗下《细胞死亡探索》在线发表美国霍普金斯大学医学院、悉德尼·金梅尔综合癌症中心、埃默里大学医学院、亚特兰大退伍军人管理局医疗中心、国家癌症研究所的研究报告，探讨了和厚朴酚对乳腺癌细胞自噬的调节作用及其分子信号传导通路。
该研究证实，和厚朴酚可增加乳腺癌细胞自噬体堆积、自噬信号传导通路关键蛋白微管相关蛋白1（MAP1）轻链3B-II（LC3B-II）转换、自噬相关蛋白表达，并促进自噬体与溶酶体融合，产生显著的生长抑制和凋亡诱导作用。抑制自噬体形成，或抑制自噬体与溶酶体融合，或敲除自噬相关基因BECN1和ATG7，都可有效增强和厚朴酚的凋亡诱导和生长抑制作用。对肿瘤抑制蛋白丝氨酸苏氨酸激酶STK11表达进行抑制，可阻止LC3B-II转换，并阻断自噬体与溶酶体的融合和溶酶体的活性。
抗疟疾药物兼自噬抑制剂氯喹可进一步增强和厚朴酚对乳腺癌细胞的抑制作用，和厚朴酚＋氯喹可有效抑制乳腺癌细胞的发生、浸润和转移能力。
因此，该研究结果表明，和厚朴酚可抑制乳腺癌细胞保护性自噬，进一步联合氯喹有望成为治疗乳腺癌的新策略。
Cell Death Discov. 2020 Sep 6. Online ahead of print.
Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment
Nethaji Muniraj, Sumit Siddharth, Marey Shriver, Arumugam Nagalingam, Sheetal Parida, Juhyung Woo, Justin Elsey, Kathleen Gabrielson, Edward Gabrielson, Jack L. Arbiser, Neeraj K. Saxena, Dipali Sharma.
Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; Emory School of Medicine, Atlanta Veterans Administration Medical Center, Atlanta, GA, USA; National Cancer Institute, Rockville, MD, USA.
Cancer cells hijack autophagy pathway to evade anti-cancer therapeutics. Many molecular signaling pathways associated with drug-resistance converge on autophagy induction. Honokiol (HNK), a natural phenolic compound purified from Magnolia grandiflora, has recently been shown to impede breast tumorigenesis and, in the present study, we investigated whether breast cancer cells evoke autophagy to modulate therapeutic efficacy and functional networks of HNK. Indeed, breast cancer cells exhibit increased autophagosomes-accumulation, MAP1LC3B-II/LC3B-II-conversion, expression of ATG proteins as well as elevated fusion of autophagosomes and lysosomes upon HNK treatment. Breast cancer cells treated with HNK demonstrate significant growth inhibition and apoptotic induction, and these biological processes are blunted by macroautophagy/autophagy. Consequently, inhibiting autophagosome formation, abrogating autophagosome-lysosome fusion or genetic-knockout of BECN1 and ATG7 effectively increase HNK-mediated apoptotic induction and growth inhibition. Next, we explored the functional impact of tumor suppressor STK11 in autophagy induction in HNK-treated cells. STK11-silencing abrogates LC3B-II-conversion, and blocks autophagosome/lysosome fusion and lysosomal activity as illustrated by LC3B-Rab7 co-staining and DQ-BSA assay. Our results exemplify the cytoprotective nature of autophagy invoked in HNK-treated breast cancer cells and put forth the notion that a combined strategy of autophagy inhibition with HNK would be more effective. Indeed, HNK and chloroquine (CQ) show synergistic inhibition of breast cancer cells and HNK-CQ combination treatment effectively inhibits breast tumorigenesis and metastatic progression. Tumor-dissociated cells from HNK-CQ treated tumors exhibit abrogated invasion and migration potential. Together, these results implicate that breast cancer cells undergo cytoprotective autophagy to circumvent HNK and a combined treatment with HNK and CQ can be a promising therapeutic strategy for breast cancer.
DOI: 10.1038/s41420-020-00315-w
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