Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shβ-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled β-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to β-catenin in nucleus, and promoted nuclear complex formation and transcription activity of β-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.
Melatonin helps to maintain circadian rhythm, exerts anticancer activity, and plays key roles in regulation of glucose homeostasis and energy metabolism. Glycosylation, a form of metabolic flux from glucose or other monosaccharides, is a common post‐translational modification. Dysregulated glycosylation, particularly O‐GlcNAcylation, is often a biomarker of cancer cells. In this study, elevated O‐GlcNAc level in bladder cancer was inhibited by melatonin treatment. Melatonin treatment inhibited proliferation and migration and enhanced apoptosis of bladder cancer cells. Proteomic analysis revealed reduction in cyclin‐dependent‐like kinase 5 (CDK5) expression by melatonin. O‐GlcNAc modification determined the conformation of critical T‐loop domain on CDK5 and further influenced the CDK5 stability. The mechanism whereby melatonin suppressed O‐GlcNAc level was based on decreased glucose uptake and metabolic flux from glucose to UDP‐GlcNAc, and consequent reduction in CDK5 expression. Melatonin treatment, inhibition of O‐GlcNAcylation by OSMI‐1, or mutation of key O‐GlcNAc site strongly suppressed in vivo tumor growth. Our findings indicate that melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O‐GlcNAcylation of CDK5.
Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth.Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were signi cantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene.Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identi ed Asn 56 as bisecting GlcNAc modi cation site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our ndings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.
Plumbagin (PLB) is the primary component of the traditional Chinese medicine Baihua Dan, and possesses anti-infection and anticancer effects, with the ability to enhance the sensitivity of tumor cells to radiation therapy. However, the anticancer effect of PLB on nasopharyngeal carcinoma and the underlying mechanisms remain unclear. In this study, we investigated the anticancer effects of PLB on nasopharyngeal carcinoma 6-10B cells and clarified its molecular mechanisms in vitro. The results showed that PLB was effective against 6-10B cells proliferation in a dose-dependent manner by inducing G2/M phase cell cycle arrest. Furthermore, our data showed that PLB induced reactive oxygen species accumulation, which inhibited the GSK3β/STAT3 pathway and arrested the G2/M phase. Therefore, our results provided new insight into the mechanism of the antitumor effects of PLB, supporting PLB as a prospective therapeutic drug in nasopharyngeal carcinoma by modulating intracellular redox balance.
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