Muniraj Nethaji, Siddharth Sumit, Shriver Marey, Nagalingam Arumugam, Parida Sheetal, Woo Juhyung, Elsey Justin, Gabrielson Kathleen, Gabrielson Edward, Arbiser Jack L, Saxena Neeraj K, Sharma Dipali
Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231 USA.
Department of Pathology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231 USA.
Cell Death Discov. 2020 Sep 6;6:81. doi: 10.1038/s41420-020-00315-w. eCollection 2020.
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 , 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 and 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.
癌细胞劫持自噬途径以逃避抗癌治疗。许多与耐药性相关的分子信号通路都汇聚于自噬诱导。厚朴酚（HNK）是一种从[具体来源未给出]中纯化得到的天然酚类化合物，最近已被证明可阻碍乳腺肿瘤发生，在本研究中，我们调查了乳腺癌细胞是否通过引发自噬来调节HNK的治疗效果和功能网络。事实上，乳腺癌细胞在HNK处理后表现出自噬体积累增加、微管相关蛋白1轻链3β-II（MAP1LC3B-II）/轻链3β-II（LC3B-II）转化、自噬相关蛋白（ATG蛋白）表达以及自噬体与溶酶体融合增加。用HNK处理的乳腺癌细胞表现出显著的生长抑制和凋亡诱导，而这些生物学过程会因巨自噬/自噬而减弱。因此，抑制自噬体形成、废除自噬体-溶酶体融合或对[具体基因未给出]进行基因敲除可有效增强HNK介导的凋亡诱导和生长抑制。接下来，我们探讨了肿瘤抑制因子丝氨酸/苏氨酸激酶11（STK11）在HNK处理细胞的自噬诱导中的功能影响。如通过LC3B- Rab7共染色和二喹啉酸-牛血清白蛋白（DQ-BSA）分析所示，STK11沉默可废除LC3B-II转化，并阻断自噬体/溶酶体融合和溶酶体活性。我们的结果例证了HNK处理的乳腺癌细胞中自噬的细胞保护性质，并提出自噬抑制与HNK联合策略将更有效的观点。事实上，HNK和氯喹（CQ）对乳腺癌细胞表现出协同抑制作用，HNK-CQ联合治疗可有效抑制乳腺肿瘤发生和转移进展。来自HNK-CQ处理肿瘤的肿瘤解离细胞表现出废除的侵袭和迁移潜能。总之，这些结果表明乳腺癌细胞通过细胞保护自噬来规避HNK，HNK与CQ联合治疗可能是一种有前景的乳腺癌治疗策略。
