New Pancreatic Cancer Treatment May Target the NF-kappaB Pathway

A recent paper described a molecular pathway linked to the increased level of the transcription factor NF-kappaB ((nuclear factor kappa-light-chain-enhancer of activated B cells) that is a hallmark of pancreatic ductal adenocarcinoma (PDAC), one of the fastest growing and most lethal forms of cancer.

The transcription factors of the NF-kappaB family are upregulated in many human cancers. NF-kappaB has roles in all stages of carcinogenesis or cancer progression, including protection from cell death, increase of cell proliferation, cell motility and metastasis, tumor inflammation, and angiogenesis. In addition, tumor cells often acquire resistance to anticancer drugs by upregulating NF-kappaB signaling.

Investigators at the Mayo Clinic (Jacksonville, FL, USA) reported in the January 3, 2013, online edition of the journal PLOS ONE that increased activity of the alternative NF-kappaB pathway resulted from suppression of TNF (tumor necrosis factor) receptor-associated factor 2, or TRAF2. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms a heterodimeric complex with TRAF1. This protein is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF1 interacts with the inhibitor-of-apoptosis proteins (IAPs), and functions as a mediator of the antiapoptotic signals from TNF receptors. Loss of TRAF2 promotes fast growth of pancreatic tumors and correlates with increased aggressiveness.

These findings were obtained by analyzing 55 human pancreatic cancer samples in which 69% demonstrated inhibition of TRAF2 and higher levels of molecules involved in the NF-kappaB pathway.

"Targeting this pathway to decrease the proliferation of cancer cells may represent a new strategy for pancreatic cancer therapy," said senior author Dr. Peter Storz, a biochemist and molecular biologist at the Mayo Clinic.

One possible chemotherapeutic agent is the drug bortezomib, which has already been approved for several human blood cancers. Bortezomib is a proteasome inhibitor, and as such blocks the production of an enzyme complex that normally plays a role in many metabolic processes related to cell growth. By doing this, the drug slows cell growth and can cause the cells to die. Although bortezomib also affects healthy cells, it has a much greater effect on cancer cells, as they are growing much more rapidly. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in cancer cells dependent upon suppression of pro-apoptotic pathways.

"Of course, this hypothesis requires extensive clinical testing, but our findings offer a new direction to investigate in improving treatment of pancreatic cancer," said Dr. Storz.

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