Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

Abstract

Our earlier work showed that Musashi (MSI)-2 promoted the development of pancreatic cancer (PC) by down-regulating Numb, which prevented murine double-minute (MDM)-2-mediated p53 ubiquitin degradation. Thus, we investigate the relationship among MSI2, Numb, MDM2, and p53 in PC and, an association that has not been reported to our knowledge. MSI2 had no relationship with mutant p53 (mtp53) and wild-type p53 (wtp53) in normal PC cells. However, in response to gemcitabine or cisplatin treatment, MSI2 silencing simultaneously down-regulated MDM2 and up-regulated Numb and wtp53 protein levels. Moreover, these 4 endogenous proteins can be coimmunoprecipitated as a quaternary complex. Numb small interfering RNA (siRNA) reversed the MSI2 silencing-induced p53 increase. During treatment with chemical agents, MSI2 silencing decreased drug resistance and cell motility and inhibited tumor growth, all of which were significantly reversed by p53 siRNA. MSI2 was also negatively associated with Numb and positively associated with MDM2 expression in tissue. Overexpression of MSI2, MDM2, and mtp53 and weak expression of Numb were closely associated with aggressive clinicopathologic characteristics and poor prognosis for patients with PC. MSI2 negatively regulates wtp53 protein by up-regulating MDM2 and down-regulating Numb after treatment with chemical agents. MSI2 promotes drug resistance and malignant biology of PC in a p53-dependent manner.-Sheng, W., Dong, M., Chen, C., Wang, Z., Li, Y., Wang, K., Li, Y., Zhou, J. Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer.

Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

“…Consistent with our previous studies [21,23], Numb knockdown significantly reversed the increase in wtp53 protein levels induced by silencing SRPK2 during oxaliplatin treatment in Capan-2 and SW1990 cells ( Fig. 7).…”

“…SRPK2 silencing significantly enhanced the level of Numb protein in PC cells (Fig. A,B), and our previous studies showed that Numb knockdown downregulated the wtp53 protein during chemical agent treatment . Thus, we inferred that silencing SRPK2 upregulated the oxaliplatin‐induced wtp53 activation via upregulating Numb protein.…”

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

“…Despite the challenges for in vivo administration, we reduced the disease burden in an aggressive MLL-AF9 leukemia model and decreased MYC levels without overt toxicity. Interestingly, it has previously been shown that MSI2 can contribute to chemotherapeutic resistance in different cancer models 42,55,56 . Future studies could examine if combination therapies could provide additional clinical benefit.…”

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

“…Fluorescence polarization (FP) assays and calculation for the Kd were carried out using our previously described methods. 26 RNA with scrambled sequence was used as the control (control 15 ). All RNAs were used at 2 nM.…”

“…The RNA-binding protein (RBP) Musashi-2 (MSI2) is overexpressed in many cancers, including colorectal adenocarcinomas, 1-3 breast, 4,5 hematologic malignancies, [6][7][8][9][10][11][12] lung, 13 glioblastoma, 14 and pancreatic cancers. [15][16][17] As such, it mediates mRNA stability and translation of proteins involved in oncogenic pathways. [18][19][20] Overexpression and knockdown studies indicate that MSI2 is a promising therapeutic target for cancer.…”