Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Ranapipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantlyincreased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinicaltrials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yetbeen fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreaticadenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates astrong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggersBeclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrialuncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggeringmitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagicstimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediatedcytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells tothe standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used incombination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our resultsshed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and supportits potential use to develop new anticancer strategies.

Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner

Fiorini, Claudia;CORDANI, MARCO;GOTTE, Giovanni;DONADELLI, Massimo
2015-01-01

Abstract

Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Ranapipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantlyincreased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinicaltrials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yetbeen fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreaticadenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates astrong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggersBeclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrialuncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggeringmitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagicstimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediatedcytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells tothe standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used incombination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our resultsshed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and supportits potential use to develop new anticancer strategies.
autophagy
onconase
pancreatic cancer
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/906183
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