转移是癌症患者死亡的主要原因，也是癌症生物学中的一个重要挑战。各种适应性分子信号通路在癌细胞的转移和次生肿瘤的形成中起着至关重要的作用。侵略性癌细胞，如三阴性乳腺癌（TNBC），更易于进行转移，因此具有较高的复发率和微小转移潜力。循环肿瘤细胞（CTC）是循环中的肿瘤细胞，提供了一种有吸引力的药物靶点，以治疗转移性疾病。 CTC的细胞周期调节和应激响应在其生存和进展中起着至关重要的作用，因此可能被认为是治疗上活跃的热点。细胞周期蛋白D /依赖于周期蛋白激酶（CDK）通路调节细胞周期检查点，这个过程在癌细胞中经常发生错乱。选择性CDK抑制剂可以通过诱导周期性阻滞来限制细胞周期调节蛋白的磷酸化，因此可能是侵略性癌细胞在原发或继发部位分裂期的有效治疗策略。然而，在漂浮状态下，癌细胞暂停其增殖过程，并通过转移的各个步骤进行。目前的研究表明，新型CDK抑制剂4ab在粘附和漂浮条件下生长的侵略性癌细胞中诱导自噬和内质网（ER）应激，从而导致副死亡。此外，我们的结果表明，4ab通过ER应激介导的JNK信号激活有效诱导侵略性癌细胞死亡。此外，观察到4ab在携带肿瘤的小鼠中的治疗显示肿瘤负担和微小转移有显着减少。这些研究的结果表明，4ab可能成为潜在的抗肿瘤和抗转移剂。4ab的图形表示：图像表示4ab在侵略性癌细胞中死亡诱导途径的影响。 4ab诱导ER应激并激活自噬，导致空泡化，从而引起侵略性癌细胞的细胞凋亡。©2023。作者经Springer Science + Business Media，LLC授权，Springer Nature的一部分。

Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.