RACK1 cooperates with NRASQ61K to promote melanoma in vivo.

Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRasQ61K mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo.

Evidence for a differential opioidergic involvement in the analgesic effect of antidepressants: prediction for efficacy in animal models of neuropathic pain?

BACKGROUND AND PURPOSE: Antidepressants are one of the recommended treatments for neuropathic pain. However, their analgesic action remains unpredictable, and there are no selection criteria for clinical use. Better knowledge of their mechanism of action could help highlight differences underlying their unequal efficacy. EXPERIMENTAL APPROACH: We compared the activity of a tricyclic antidepressant (clomipramine) with selective 5-HT and noradrenaline reuptake inhibitors (milnacipran and duloxetine) in streptozocin-induced diabetic and chronic constriction nerve injury-induced neuropathic rats, after repeated injections. We looked for an opioidergic mechanism in their action. KEY RESULTS: Abolition of mechanical hyperalgesia was observed in mononeuropathic rats after five injections of clomipramine (5 mg·kg(-1) , s.c.) and milnacipran (10 or 20 mg·kg(-1) , i.p.) and in diabetic rats after clomipramine. An additional antinociceptive effect was obtained with five injections of duloxetine (3 mg·kg(-1) , i.p.) in both models and milnacipran (10 mg·kg(-1) , i.p.) in diabetic rats. These effects were observed with plasma antidepressant concentrations similar to those found in patients treated for neuropathic pain. Naloxone (1 mg·kg(-1) , i.v.) only suppressed the anti-hyperalgesic effects of clomipramine in both models of pain and of milnacipran in the traumatic model. CONCLUSIONS AND IMPLICATIONS: The opioid system appears to be involved in the mechanism of action of antidepressants that only have an anti-hyperalgesic effect but not in those that have a stronger (i.e. antinociceptive) effect. These differences between the antidepressants occurred whatever the aetiology of the neuropathy and, if confirmed in clinical trials, could be used to decide which antidepressant is administered to a patient with neuropathic pain.