Distinct inhibitory efficiency of siRNAs and DNAzymes to β1 integrin subunit in blocking tumor growth.

Abstract

Receptors of the β1 integrin family are involved in many tumor-promoting activities. There are several approaches currently used to control integrin activity, and thus to potentially restrain tumor metastasis and angiogenesis. In this study, we compared inhibitory efficiencies of siRNA and DNAzymes against the β1 integrin subunit (DEβ1), in a mouse xenograft model. Both inhibitors were used under their most favorable conditions, in terms of concentrations, incubation time and lack of cytotoxic effects. Transfection of siRNAβ1 or DEβ1 remarkably inhibited the growth of both PC3 and HT29 colon cancer cells in vitro, and decreased their capability of initiating tumor formation in the mouse xenograft model. siRNAβ1 appeared to be slightly more efficient than DEβ1 when tested in vitro, however it was comparably less proficient in blocking the tumor growth in vivo. We conclude the DNAzyme, due to its greater resistance to degradation in extra- and intracellular compartments, to be a superior inhibitor of tumor growth in long lasting experiments in vivo when compared to siRNA, while the latter seems to be more efficient in blocking β1 expression during in vitro experiments using cell cultures.

The nuclear orphan receptor NR4A1 regulates β1‐integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists

“…Our recent study showed that these NR4A1 ligands also inhibit breast cancer cell migration through inhibition of β1‐integrin expression which is an NR4A1‐regulated gene in breast cancer cells . There is also evidence that β1‐integrin is a negative prognostic factor for colon and pancreatic patients and plays an important role in cancer cell migration/invasion and metastasis . It was evident from the results of RNAi studies that decreased expression of NR4A1 resulted in decreased expression of β1‐integrin RNA and protein, α5‐integrin, and a β1‐integrin‐activated FAK gene phosphorylation (Figs.…”

“…29 There is also evidence that β1-integrin is a negative prognostic factor for colon and pancreatic patients and plays an important role in cancer cell migration/invasion and metastasis. [30][31][32][33][34][35][36][37][38][39][40][41] It was evident from the results of RNAi studies that decreased expression of NR4A1 resulted in decreased expression of β1-integrin RNA and protein, α5-integrin, and a β1-integrin-activated FAK gene phosphorylation (Figs. 1A,B and 2A,E).…”

“…12,14,19,[26][27][28] Recent studies have identified β1-integrin as an NR4A1regulated gene in breast cancer cells and the NR4A1 antagonist DIM-C-pPhOH decreases β1-integrin expression and also inhibits β1-integrin-dependent cell migration. 29 Since β1-integrin is a negative prognostic factor and induces migration/invasion and metastasis in both pancreatic and colon cancer cells, [30][31][32][33][34][35][36][37][38][39][40][41] this study investigated the role of NR4A1 in regulating β1-integrin expression and subsequent inhibition of β1-integrin-dependent migration/ invasion by C-DIM/NR4A1 antagonists. The results confirm that C-DIM/NR4A1 antagonists target NR4A1 and inhibit invasion of pancreatic and colon cancer cells, demonstrating that these compounds represent a novel class of mechanism-based drugs for pancreatic and colon cancer chemotherapy.…”

Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells

“…myc plays a central role in regulating proliferation and survival of normal cells and CSC and connects malignancy with stemness (39), was also overexpressed in HT29-resistant cells. Receptors of the β1 integrin family are involved in many tumor-promoting activities (73), and overexpression of ITGβ-1 has been reported in hepatocellular carcinoma (HCC) (41) and esophageal squamous cell carcinoma (40). It has been associated with resistance to apoptosis via the activation of a mAP kinase-dependent pathway.…”

Deoxyribozymes as Catalytic Nanotherapeutic Agents

“…mb1DE also reduced angiogenesis and xenograft growth following intratumoral administration without a carrier (72). DNAzyme was more proficient than siRNA in blocking colon adenocarcinoma and prostate carcinoma growth even in circumstances where 5-fold less DNAzyme was delivered than siRNA (73). Recently, Zhang and colleagues used a TACE strategy to deliver VEGFR1 DNAzymes into tumors in a rabbit hepatocellular carcinoma model and observed suppression of VEGFR expression and tumor microvascular permeability (56).…”