In a study with five patient-derived glioma stem cell-enriched cell lines, the authors have reported that p21 and p27 operate both as tumor suppressors, limiting cell proliferation, but also as oncogenes, conferring cell resistance to DNA damage and developing drug resistance [189]. of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as Ciprofloxacin HCl a therapeutic target. (TGF-mediated breast cancer cell migration and invasion, whereas its gene silencing blocked the tumor invasion in a mammary fat Ciprofloxacin HCl pad xenograft mouse model and various triple negative breast cancer cell lines, without alterations in cell growth and proliferation [136]. In this study high p21 expression was correlated with poor overall and distant metastasis free survival of breast cancer patients promoting migration/invasion at the transcriptional level [136]. Moreover, the complex of nuclear p21 and cyclin D1 is involved in actin remodeling of TGF-triple-knockout mice did not develop spontaneous tumors until the age of 500 days, suggesting the existence of additional pathways serving as mediators of p53-driven tumor suppression [171]. In sum, loss of p21 has differential effects on tumorigenesis based on the specific cellular context and the Cav1 genetic background. 3.3. Ciprofloxacin HCl Considering p21 in Cancer Therapy Given p21s antagonistic duality [51] in various cellular processes (Table 1), it is obvious that p21 can have a dual role in tumor development and progression relying on the cancer type, the p53 status and the used chemotherapeutics. It can serve as a biomarker for specific therapies or prognosis, partially depending on its subcellular localization. In fact, the induction of p21 has been used as a drug response parameter [16]. Simply interfering with p21 as anti-cancer therapy bears risks and undesired side effects. First, increasing p21 can cause senescence, a supposed permanent growth arrest [172], which was believed to be only tumor suppressive terminating tumor regression, and is now regarded as a tumor promoter [173]. Senescent cells secrete numerous soluble factors promoting tissue repair, invasiveness of neighboring cells, chronic inflammation and tumor progression [174], and contribute to the escape of drug-induced apoptosis [175]. We examined the therapeutic potential of p21 in the context of Ciprofloxacin HCl Poloxin, a well-studied Polo-like kinase 1 (Plk1) inhibitor [176,177]. Plk1, a highly conserved serine/threonine kinase with critical roles during mitosis, is overexpressed in various tumor entities serving as a poor prognostic marker [178] and is thus considered as a promising target for molecular cancer therapy [179]. Cancer cells without p21 showed a stronger mitotic arrest accompanied by proliferation inhibition, more DNA damage and apoptosis induction upon Poloxin treatment relative to cancer cells with functional p21 and p53, which displayed a cytoplasmic re-localization and an anti-apoptotic feature [176]. Interestingly, long-term treatment (four days) of HCT116 p21+/+ cells with Poloxin led to senescence, whereas strong apoptosis induction was observed in cells lacking p21 [48]. Similar effects were detected in HCT116 cells treated with low doses of the anti-cancer drug camptothecin for four days [180]. Conversely, there are studies where overexpressed p21 enhanced the apoptotic response upon cisplatin treatment [181,182,183]. Remarkably, cellular senescence contributes to therapy resistance [184] and an aggressive tumor relapse by undergoing an epigenetic reprogramming of senescent cells into a stemness-like state [173,185]. In support of this observation, sustained expression of p21 exhibits oncogenic functions in a p53-null background leading to escaping senescence and chemoresistance [62]. Cells bypassing senescence display an increased genomic instability pointing again to p21s two-faced involvement as genome guardian versus genomic instability mediator [186]. This Ciprofloxacin HCl duality is commonly attributed to the cellular or environmental context in which tumors develop. The mechanistic basis underlying such context-dependent phenomena remains to be defined in most cases, and its elucidation is essential for both understanding cell biology and the rational design of cancer therapy [187]. Thus, for therapeutic approaches, simply increasing p21 may not be beneficial and could provoke opposite undesirable/unintended outcomes. Second, considering p21s role in the cell cycle, stem cell differentiation and EMT of tumor cells, depleting p21 may result in either tumor suppressive or oncogenic effects depending on the cellular context. Cancer stem cells have been suggested to promote tumorigenesis as seeds for metastasis [188]. p21 is indispensable for maintaining self-renewal of leukemia stem cells [88], and it is able to inhibit oncogene-induced EMT and breast tumor stem cells in transgenic mice [101]. In a study with five patient-derived glioma stem cell-enriched cell lines, the.