Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment
Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment
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DOI：
10.1038/s41420-020-00315-w
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发表时间：
2020-09-06
影响因子：
7
通讯作者：
Sharma, Dipali
中科院分区：
文献类型：
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作者：
Muniraj, Nethaji;Siddharth, Sumit;Sharma, Dipali
癌细胞劫持自噬途径以逃避抗癌治疗。许多与耐药相关的分子信号通路都集中在自噬诱导上。檀香木（HNK），一种天然的酚类化合物纯化从木兰花，最近已被证明可以阻止乳腺肿瘤的发生，在本研究中，我们研究了乳腺癌细胞是否引起自噬，以调节治疗效果和功能网络的HNK。事实上，乳腺癌细胞在HNK处理后表现出增加的自噬体积累、MAP 1 LC 3B-II/LC 3B-II转化、ATG蛋白的表达以及自噬体和溶酶体的融合增加。用HNK处理的乳腺癌细胞表现出显着的生长抑制和凋亡诱导，并且这些生物学过程被宏自噬/自噬减弱。因此，抑制自噬体的形成，消除自噬体-溶酶体融合或基因敲除BECN 1和ATG 7有效地增加HNK介导的凋亡诱导和生长抑制。接下来，我们探索了肿瘤抑制因子STK 11在HNK处理的细胞中自噬诱导中的功能影响。STK 11沉默消除了LC 3B-II转化，并阻断了自噬体/溶酶体融合和溶酶体活性，如LC 3B-Rab 7共染色和DQ-BSA测定所示。我们的研究结果证实了HNK处理的乳腺癌细胞中自噬的细胞保护性质，并提出了自噬抑制与HNK的组合策略将更有效的概念。事实上，HNK和氯喹（CQ）显示出对乳腺癌细胞的协同抑制，并且HNK-CQ组合治疗有效地抑制乳腺肿瘤发生和转移进展。来自HNK-CQ处理的肿瘤的肿瘤解离细胞表现出废除的侵袭和迁移潜力。总之，这些结果暗示乳腺癌细胞经历细胞保护性自噬以绕过HNK，并且HNK和CQ的组合治疗可以是乳腺癌的有希望的治疗策略。
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 fromMagnolia 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 ofBECN1andATG7effectively 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.