Abstract
Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1α protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1α is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co-activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor.
Highlights
Pancreatic Ductal Adenocarcinoma (PDAC) is among the most notorious cancers with a poor 5-years survival rate of 7%1
The KrasG12DTP53R172HPdx-Cre (KPC) mouse model of pancreatic cancer recapitulates the stages of pancreatic tumor progression as seen in patients23. 1 month tumor is typically representative of early tumor without manifestation of disease, 3 month represents a intermediate stage with extensive panIN lesions while 6 month or full tumor is an advanced tumor stage
Our results indicated that upon treatment of pancreatic tumors derived from patients or the genetically engineered KRASG12D; Trp53R172H; Pdx-1Cre (KPC) mice,Minnelide decreased hypoxia in the tumor
Summary
Pancreatic Ductal Adenocarcinoma (PDAC) is among the most notorious cancers with a poor 5-years survival rate of 7%1. In addition to preventing efficacious delivery of chemotherapeutic compounds to the tumor, the robust stroma in pancreatic cancer results in generation of hypoxic niches within the tumor, which trigger activation of hypoxia mediated pro-survival pathways[7, 8]. Enzymatic activity of PHDs is inhibited owing to less production of TCA cycle intermediate αKG This results in attenuated hydroxylation of HIF-1α, leading to its accumulation[10]. Minnelide has shown promise in a recently concluded Phase 1 trial for advanced GI malignancies and is currently awaiting a Phase 2 trial in pancreatic cancer[19] In this context, it is important to understand the mechanism by which Minnelide induces pancreatic tumor regression
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