Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
Toxicol Appl Pharmacol. 2019 Jan 1;362:116-124. doi: 10.1016/j.taap.2018.10.020. Epub 2018 Oct 24.
The capacity of cancer cells to resist detachment-induced apoptosis, i.e. anoikis, as well as anchorage-independent growth are crucial prerequisites for tumor metastasis. Therefore, agents interfering these properties may provide novel anti-metastatic strategies. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is known as a potent chemopreventive agent, but its effect on anoikis resistance has not been investigated. In this study, two non-small cell lung cancer (NSCLC) cell lines, A549 and CL1-5 cells, were treated with SFN under either suspension or adhesion conditions. SFN exhibited more potent cytotoxicity against suspending rather than adherent cancer cells. The selective cytotoxicity was due to the induction of anoikis, as evident by chromatin condensation, Annexin V binding, and activation of the mitochondrial apoptotic pathway. SFN also inhibited NSCLC cell to form spherical colonies, suggesting that anchorage-independent growth was prevented by SFN. Consistently, SFN treatment led to inactivation of FAK and Akt, down-regulation of β-catenin, and up-regulation of the cyclin-dependent kinase inhibitor p21. Because A549 cells with wild-type p53 are more sensitive to SFN than p53-mutant CL1-5 cells, p53 dependency of SFN responses were determined in p53-knockdown A549 cells. Knockdown of p53 attenuated the ability of SNF to inhibit anoikis resistance and sphere formation in A549 cancer cells, suggesting that the presence of p53 in NSCLC cancer cells is involved in the sensitivity to SFN. These results provide new insight into mechanisms underlying the chemopreventive ability of SFN and suggest a potential benefit of SFN to interfere with tumor metastasis.
癌细胞抵抗失巢凋亡（即 anoikis）以及锚定非依赖性生长的能力是肿瘤转移的关键前提条件。因此，干扰这些特性的药物可能提供新的抗转移策略。硫代葡萄糖苷（SFN）是十字花科蔬菜中发现的一种异硫氰酸盐，是一种有效的化学预防剂，但它对 anoikis 抵抗的影响尚未被研究。在这项研究中，两种非小细胞肺癌（NSCLC）细胞系 A549 和 CL1-5 在悬浮或粘附条件下用 SFN 处理。SFN 对悬浮癌细胞的细胞毒性比粘附癌细胞更强。这种选择性细胞毒性是由于诱导 anoikis 所致，这可以通过染色质浓缩、Annexin V 结合和线粒体凋亡途径的激活来证明。SFN 还抑制 NSCLC 细胞形成球形集落，表明 SFN 阻止了锚定非依赖性生长。一致地，SFN 处理导致 FAK 和 Akt 的失活、β-catenin 的下调以及细胞周期蛋白依赖性激酶抑制剂 p21 的上调。由于具有野生型 p53 的 A549 细胞比 p53 突变的 CL1-5 细胞对 SFN 更敏感，因此在 p53 敲低的 A549 细胞中确定了 SFN 反应的 p53 依赖性。p53 敲低减弱了 SFN 抑制 A549 癌细胞 anoikis 抵抗和球体形成的能力，表明 NSCLC 癌细胞中 p53 的存在与 SFN 的敏感性有关。这些结果为 SFN 的化学预防能力的机制提供了新的见解，并表明 SFN 具有干扰肿瘤转移的潜在益处。
