Formyl peptide receptor 1 signaling strength orchestrates the switch from pro-inflammatory to pro-resolving responses: The way to exert its anti-angiogenic and tumor suppressor functions

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The well-paced trigger of inflammation resolution following an inflammatory response is crucial for tissue homeostasis and cancer. In gastrointestinal tumors the Formyl peptide receptor 1 (FPR1) stimulates an inflammation resolution response able to restrain cancer angiogenesis and growth. A preceding inflammatory signal is necessary for the induction of the pro-resolving response. However, if FPR1-induced inflammation resolution and tumor suppressor function require an early pro-inflammatory trigger and how this is achieved remains unknown. A ROS-dependent signaling is activated in response to FPR1 activation. In colorectal carcinoma (CRC) cells, we carefully analyzed this signal showing that FPR1 activation by the fMLF peptide induces biphasic ROS production: a first wave, early, mitochondrial (mROS), followed by a second, late, NADPH oxidase (NOX1)-dependent. mROS cause SHP2 phosphatase inactivation restraining its ability to dephosphorylate and inactivate SRC. SRC, in turn, allows the activation of RAS and Rac1 GTPases. RAS activates MAPK signaling, while Rac1 supports NOX1 activation, that causes the second wave of ROS, reinforcing this signaling cycle. Importantly, for the first time, we demonstrate that mROS production precedes and is necessary for pro-inflammatory mediators’ release, while NOX1-dependent ROS are only required for pro-resolving mediators’ synthesis. Pharmacological and genetic approaches and functional assays show that this signaling cascade is essential for the pro-resolving and anti-angiogenic properties of FPR1 in CRC. In conclusion, we show that FPR1 elicits pro-resolving effects in CRC activating two waves of ROS production characterized by different strength and kinetics, that parallel and are necessary for pro-inflammatory or pro-resolving mediators’ production. For the first time we observed that FPR1 activation induces two time- and source-distinguishable waves of ROS production in colorectal carcinoma (CRC) cells: a first rapid mitochondrial-derived ROS production (mROS); a second late wave, dependent from the first, due to the activation of NOX1. mROS trigger SHP2 phosphatase inactivation, and this event in turn allows the activation of SRC. SRC activity enables the activation of two small GTPase: i) RAS, which activates the classic MAPK cascade; ii) Rac1, which functions as an essential factor to mount the NOX1 active complex on the cell membranes in the CRC system. The addition of NOX1-dependent ROS (red arrows) to mROS (black arrows) helps to reach the critical threshold of MAPK activation, which is required for ALOX transcription and SPMs production. This implies that the entity and/or duration of MAPK activation results in distinct transcriptional outputs that activate pro-inflammatory or pro-resolving responses. • FPR1 induces a rapid mitochondrial and a late NOX1-dependent ROS production. • FPR1 exploits SHP2 phosphatase inactivation to exert its antitumor activity. • FPR1 induced mitochondrial ROS trigger inflammation, NOX1-ROS initiate resolution.

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