Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells

Abstract

Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab. TP53 wild-type myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both nongenotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increased DR5 expression only in TP53 wild-type cells and synergistically increased lexatumumab efficiency yet did not increase DR4 expression, nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin-3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin-3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin-3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5 but not DR4 and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy.

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

“…TRAIL, which induces apoptosis via interactions with its death receptors DR4 and DR5, represents a promising candidate agent for the treatment of MM (11,42,43). Recent studies suggest that there is a correlation between TRAIL sensitivity and death receptor expression in cancer cells (44), thus the upregulation of death receptor expression renders MM cells more sensitive to the action of TRAIL.…”

Curcumin induces cell death of the main molecular myeloma subtypes, particularly the poor prognosis subgroups

“…8 Interestingly, taking all HCMLs together (median LD 50 =20.5 mM), we found that most HMCLs were efficiently killed by curcumin; we observed that 16 HMCLs were highly sensitive (LD 50 < 20.5 mM), and 6 HMCLs exhibited intermediate LD 50 values (20.5 mM LD 50 < 32.2 mM); only 7 HMCLs exhibited the highest LD 50 values (32,2 < LD 50 < 56 mM). Moreover, curcumin sensitivity was not dependent on TP53 status, since LD 50 were not statistically different between HMCLs exhibiting either wild type (median LD 50 18.4 mM) or abnormal TP53 (mutated, truncated or deleted) 12 (median LD 50 22.15 mM) (p=0.221) (Fig. 1C).…”

“…12,22 The HMCLs BCN; NAN1, ¡3, ¡7, ¡8 and ¡9; SBN; and XG1, ¡2, ¡5, ¡6, ¡7 and ¡11 were derived in Nantes or Montpellier laboratories in the presence of interleukin-6 (IL-6). KMS11, KMS12-PE and KMM1 HMCLs were kindly provided by Dr. Otsuki (Kurashiki, Japan), JJN3 was kindly provided by Dr. Van Riet (Brussels, Belgium), JIM3 was kindly provided by Dr. MacLennan (Birmingham, UK), Karpas 620 was kindly provided by Dr. Karpas (Cambridge, UK) and MM1S was kindly provided by Dr. Rosen (Chicago, IL).…”

“…12,13 As shown in Figure 2, dot plots illustrated the loss of CD138 staining in primary cells from sample 4 under curcumin treatment. We found that primary cells, from MM or secondary plasma cell leukemia, were efficiently killed by 20 mM curcumin ( Table 2).…”

Induction of Indoleamine 2,3-dioxygenase (IDO) Enzymatic Activity Contributes to Interferon-Gamma Induced Apoptosis and Death Receptor 5 Expression in Human Non-small Cell Lung Cancer Cells

“…Some studies have reported that certain intracellular molecules can selectively affect the expression of different death receptors. For example, inhibition of p53 expression affects the expression of DR5 but not that of DR4 in myeloma cells (Surget et al, 2012). Thus, further clarification on the mechanism underlying IDO activity-regulated DR5 expression and further research is still needed.…”