Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol

Abstract

Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol

The BH3-only protein Noxa is stimulated during apoptosis of chronic lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract

“…3A. As expected (15), flavopiridol-induced PARP-1 and p27 cleavages were associated with a strong Mcl-1 inhibition, a slight Bcl-2 cleavage and no stimulatory effect on Noxa levels. As also expected (15), hyperforin elicited PARP-1, p27 kip1 and Bcl-2 cleavages to a lesser extent than flavopiridol, did not inhibit Mcl-1 but strongly enhanced Noxa levels.…”

“…Consequently, the mechanism of action of M2Yn is different from that of flavopiridol and other plant-derived compounds acting through downregulation of antiapoptotic proteins including Mcl-1 (12,13). By upregulating the proapoptotic Noxa, M2Yn employs a mechanism shared by hyperforin, proteasome and HDAC inhibitors (15,17,18,32). This effect appears to result from a regulation at the protein level, as suggested by the ability of M2Yn to inhibit proteasomal activity in CLL cells, as do proteasome inhibitors (17) and hyperforin (Zaher et al, unpublished).…”

“…Besides, loss of Mcl-1 is sufficient by itself to trigger programmed cell death (31). Due to its specific interaction with Mcl-1, the BH3-only Noxa seems also to be an interesting target for CLL therapy (15,16,32). Actually, Noxa antagonizes Mcl-1, thus facilitating the activation of Bak, responsible for the mitochondrial membrane permeabilization and the subsequent caspase cascade.…”

“…By its capacity to inhibit short-lived protein mRNA transcription, flavopiridol (and other cyclindependent kinase inhibitors) downregulates antiapoptotic proteins which are overexpressed in leukemic cells, including Mcl-1 (12,13), a Bcl-2 family member thought to be crucial for apoptosis deficiency in CLL (14). In contrast to flavopiridol, hyperforin does not inhibit Mcl-1 but induces the expression of the proapoptotic protein Noxa (15) belonging to the BH3-only subclass of the Bcl-2 family (16). Proteasome and HDAC inhibitors also upregulate Noxa (17,18).…”

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

“…Like most CLL cell apoptosis inducers, hyperforin triggers the caspasedependent mitochondrial pathway (19) but the molecular mechanisms allowing the liberation of apoptogenic factors from mitochondria are not elucidated. In a preliminary study, we found that Noxa protein is upregulated during apoptosis of CLL cells induced by hyperforin but not flavopiridol (23 In the present study, we first characterized this Noxa upregulation and then provided evidence favoring that Noxa is involved in the mechanism of action of the phloroglucinol through interaction with Mcl-1, displacement of the proapoptotic protein Bak from its complex with Mcl-1 and Bak activation, responsible for mitochondrial membrane permeabilization. Our data thus strengthen the concept of targeting the BH3-only protein Noxa for CLL therapy.…”