Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Abstract

There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

Structure–Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity

“…53 Furthermore, other studies indicated that DDX5 is not only involved in glucose metabolism but also in lipid and nucleotide metabolism in cancer. 51 Consistent with these observations, RNA-Seq analysis indicated that the metabolism of glucose (Figures 12 and S11), nucleotides (Figures 13 and S12), and lipids (Figure 14) has been significantly reduced under FL118, FL77-6, FL77-9, and FL77-24 treatment.…”

“…We found that concentration as high as 2.5 μM could not inhibit TOP1 activity, although 2.5 μM is still unable to be reached in a physiological condition. In other words, since DDX5/TOP1/TOP2/TOP3B is in the same protein complex, and FL118 mainly binds to DDX5, we conclude that FL118, FL77-6 , FL77-9, and FL77-24 in nonphysiological high concentrations may bind to TOP1. Our study not only confirmed the results of previous studies for CPTs related to TOP1 inhibition but we have also demonstrated that FL118, FL77-6 , FL77-9, and FL77-24 inhibition of TOP1 is not the primary MOA for these novel drugs.…”

“…This question opens an intriguing window for further follow-up studies. While we do not currently know why, a rational answer could be easily obtained based on DDX5′s multiple function features in cancer . Specifically, DDX5 can physically act with many different protein regulators, and thus, DDX5 has a large protein complex when DDX5 executes its particular function in a specific process.…”

“…52 DDX5 is involved in innate immune suppression in multiple ways. 51 Based on these findings, degradation of DDX5 by FL118 should activate innate immune response. Consistent with this rationale, treatment of HCT116 cells with FL118, FL77-6, FL77-9, and FL77-24 activates innate immune response in multiple pathways, which include, but may not be limited to, the direct or indirect induction of the expression of the antiviral APOBEC3G gene and the innate immunity-stimulatory genes including the genes for CASP1, CXCR2, IFIH1, IL-12A, IL-12B, IL-12RB2, IL-1A, IRF1, 3, 5, and 7 (Figure 11).…”

“…Together, these observations suggest that DDX5 is likely a center molecule involved in a broad network of DDX and TOP family members which control DNA topological changes and DNA repair (see below), which have been demonstrated with growing evidence in the literature. 51 Activation of Cancer Cell Apoptosis and DNA Damage Pathways by FL118, FL77-6, FL77-9, and FL77-24. Our previous studies found that treating cancer cells with FL118 induced apoptosis by the FL118-mediated inhibition of multiple antiapoptotic proteins (e.g., survivin, Mcl-1, XIAP, and cIAP2) and induction of pro-apoptotic proteins (e.g., Bax and Bim).…”