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Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer

Kaiyu Yuan¹, Sun Yong¹, Fei Xu¹

¹Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.

|August 31, 2015

Abstract:

Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between -295 to -300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy.

Insights

Calmodulin antagonists like TFP and TMX enhance TRAIL-R2-induced apoptosis in resistant pancreatic cancer cells. These drugs increase DR5 expression and promote cell death, offering a new therapeutic strategy.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Pancreatic cancer exhibits high malignancy, limited treatment options, and poor prognosis.
TRAIL-activating therapy shows promise but faces resistance in pancreatic cancers.
Calmodulin (CaM) antagonists are investigated for their potential to overcome this resistance.

Purpose of the Study:

To investigate the effects of CaM antagonists (TFP, TMX) on TRAIL-R2-induced apoptosis in TRAIL-R2-resistant pancreatic cancer cells.
To elucidate the underlying molecular mechanisms of CaM antagonist action.
To evaluate the in vivo efficacy of combined therapy.

Main Methods:

Utilized TRAIL-R2-resistant PANC-1 cells for in vitro apoptosis assays.
Administered TFP and TMX alone and in combination with TRAIL-R2.
Analyzed the composition and signaling of the death-inducing signaling complex (DISC).
Assessed in vivo tumorigenesis using TMX and TRAIL-R2 therapy.
Performed molecular analysis of the DR5 gene promoter region.

Main Results:

TFP and TMX alone did not induce apoptosis but dose-dependently enhanced TRAIL-R2-induced apoptosis.
TMX treatment improved TRAIL-R2 therapy efficacy in vivo.
CaM antagonists inhibited survival signals (CaM/Src) in the DISC while promoting apoptotic signals (caspase-8).
TFP/TMX increased DR5 expression by interacting with a specific region in the DR5 gene promoter.
Caspase-8 inhibition abrogated the sensitizing effects of TFP/TMX.

Conclusions:

Calmodulin antagonists enhance TRAIL-R2-induced apoptosis in resistant pancreatic cancer by modulating DISC composition and increasing DR5 expression.
These findings support the combination of CaM antagonists with TRAIL-activating agents for pancreatic cancer treatment.
Readily available CaM antagonists offer a potential strategy to improve pancreatic cancer therapy outcomes.

Read full analysis

Keywords:

apoptosis calmodulin antagonists death receptor 5 pancreatic cancer resistance

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