PS1453 CURCUMIN INHIBITS PROLIFERATION AND INDUCES APOPTOSIS IN JAK2 MUTATED CELLS THROUGH THE INHIBITION OF JAK2/STAT AND MTORC1 PATHWAYS

• Published in: HemaSphere Vol. 3; no. S1; pp. 668 - n/a
• Main Authors: Petiti, J., Rosso, V., Iacono, M. Lo, Panuzzo, C., Fava, C., Cilloni, D.
• Format: Journal Article
• Language: English
• Published: 01.06.2019
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000564076.45275.a1

Background: Myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive and negative. The JAK2 V617F is the most common mutation in Philadelphia negative patients and results in a constitutive activation of the JAK/STAT pathway, conferring a proliferative advantage and apoptosis inhibition. Furthermore, recent studies identified a functional crosstalk between the JAK/STAT and mTOR pathways. Given the heterogeneous clinical needs of MPNs patients, identification of an effective therapy is often difficult. Therefore, the availability of new therapeutic approaches might be very attractive. Curcumin is the active phytochemical component of the Curcuma longa plant. Previous studies showed that curcumin can suppress JAK2/STAT signaling pathways in different type of cancer and injuries. Aims: In this study, we investigated the anti‐proliferative and pro‐apoptotic effects of curcumin in JAK2 V617F cell line and in primary cells. Methods: HEL cell line and cells from patients affected by myeloproliferative neoplasms have been incubated with increasing concentrations of curcumin for different time. Apoptosis and proliferation were evaluated. Subsequently, JAK2/STAT and AKT/mTOR pathways were investigated at both RNA and protein levels. Results: We showed that curcumin strongly inhibited the proliferation and induced apoptosis in a dose and time dependent manner in HEL cells. Furthermore, we found that curcumin markedly reduced JAK2 phosphorylation and, consequently, the activation of its downstream effectors STAT3 and STAT5 in HEL cells. We observed that JAK2/STAT inhibition induced the down regulation of Pim family members in HEL cell line and in patient specimens. Farther, our results in HEL cells showed that curcumin negatively regulated the mTORC1 complex formation. As a consequence, we observed a strong inhibition of mTORC1 downstream effectors 4eBP1 and p70s6K phosphorylation. Our preliminary data on cells from MPNs patients showed that the in vitro curcumin treatment significantly promoted apoptosis and reduced the expression of Pim family members, bringing back their mRNA expressions to comparable levels with healthy subjects ones. Furthermore, the curcumin effect was strengthened by the observation that CD177, an antigen over expressed in neutrophils of the majority of MPNs patients, was down regulated by curcumin. Summary/Conclusion: In conclusion, the present study showed that curcumin exerts an antitumor effect on human JAK2 mutated cells by inducing apoptosis and inhibition of proliferation, through the regulation of both JAK2/STAT and mTORC1 pathways. These findings suggest that curcumin seems to be a promising nutraceutical compound that should be further evaluated in different pharmaceutical formulation for the treatment of MPNs.