Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs

General Questions

What is Ionizing Radiation?

Ionizing radiation consists of subatomic particles or electromagnetic waves that are energetic enough to detach electrons from atoms or molecules, ionizing them.

Two of the most common forms of ionizing radiation are gamma rays and x-rays. Both forms of ionizing radiation are almost identical with exception to their source of origination.

How is Ionizing Radiation Generated?

Ionizing radiation comes from radioactive sources such as cobalt 60 and cesium 137 and non-radioactive sources such as x-ray tubes. Radioactive sources are unstable materials where gamma rays originate from the nucleus. x-rays originate in the electron fields surrounding the nucleus or are machine-produced.

What is Ionizing Radiation Used for?

Because of the penetrating properties of ionizing radiation and their ability to kill microorganisms, ionizing radiation is used to sterilize or reduce the microbial load of many different types of products such as medical devices, packaging, cosmetics, foods, and agricultural products. It is also used to alter the properties of many different polymers through recombination, cross-linkage, and cross scission.

Why use x-ray versus gamma produced Ionizing radiation?

Gamma ionizing radiation is produced by radioactive sources such as cobalt 60 or cesium 137 and is dangerous requiring heavy shielding and high levels of security to protect. The unstable material is constantly decaying and cannot be turned off. x-ray ionizing radiation is produced by a x-ray tube therefore it can be turned off when it is not being used and it requires much less shielding. At the end the of unit’s lifecycle, the unit does not have any radioactive source and therefore does not require the expensive disposal costs associated with radioactive sources that continue to degrade over hundreds of years.

Does the RS 3400 require external cooling?

No, the RS 3400 uses a self-contained water to air exchange system.

Is the RS 3400 Blood Irradiator cleared by the FDA for GVHD?

Yes, the RS 3400 was cleared by the USFDA for marketing for the irradiation of blood for the prevention of graft verses host disease (GVHD).

How does the RS 3400 differ from other x-ray irradiators?

The RS 3400 is designed to have the blood bags rotate around the Quastar™ x-ray emitter using our patented carousel and therefore delivers superior uniformity.
Unlike other x-ray blood irradiators, the RS 3400 is completely self-contained and requires no external water supply for tube cooling.
The RS 3400 is engineered for extreme reliability as it uses the proven Quastar™ x-ray emitter.
The RS 3400 has only ONE x-ray tube and ONE power supply.

How does the RS 3400 differ from a Cs-137 gamma irradiator??

The RS 3400 uses a Rad Source patented Quastar™ x-ray emitter and therefore contains NO radioactive isotopes. It can be turned on and off, similar to a light bulb. As a result, there is no Nuclear Site License, Homeland Security issues, or room shielding requirements.

Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.

“WiDr and D54 cell lines were cultivated in MEM with 10% FBS and 1% P/S.. Mice were exposed to 5.5 Gy total body irradiation using the Rad Source Technologies X-ray RS-2000 Biological Irradiator operating at 160 kVp and 25 mA at a dose rate of 2.20 Gy/min.. Mice were fed Uniprim for the entire duration of the experiment.”

(Oncotarget 2016 Feb 29)