Pancreatic Cancer: Role of STAT-3 and Intervention of STAT-3 by Genistein

Abstract

Pancreatic cancer (PC) is a cancer that is initiated in the pancreas and spreads rapidly to other organs. Pancreatic cancer is the third most leading cause of cancer-related deaths in the United States (US) and is often regarded as one of the deadliest cancers with 95% mortality within 5 years of detection, which is the highest compared to the rest of any cancer-related deaths. Pancreatic cancer is tough to diagnose at early stages, and by the time the patient is hospitalized and detected with pancreatic cancer, it is already in advanced stages. Apart from surgical procedures, inhibition of many key proteins that are tumorigenic pathways has been tested in several model systems including mouse and are further corroborated in various clinical studies. Included in that group of several tumorigenic proteins is the signal transducer and activator of transcription 3 protein, namely, STAT-3. STATs were identified in the year 1994 that traffic signals from the activated cell surface receptors internally to the nucleus and act as potent transcription factor (TF) that regulates several key aspects of intracellular functioning, namely, cell proliferation, cell differentiation, apoptotic cell death, and angiogenesis. In normal cells, STATs are in non-phosphorylated, inactive form, but upon external stimuli, they are phosphorylated and activated that leads to translocation to the nucleus and act as transcription factors. In the STAT family, STAT-3 functions are most important as STAT-3 knockout are lethal and mice are reported to die at day 7.5. STAT-3 inhibition by RNAi or chemical compound in vivo in model systems such as mice led to a block in ductal adenocarcinomas and PanIN formation. Mouse models expressing endogenous mutant Kras mutation, STAT-3 found to phosphorylated and significantly activated. Due to STAT-3 established role in angiogenesis, several chemical and natural compounds have been developed and tested over the last two decades. STAT-3 inhibitors such as nexrutine, crizotinib, and miR-216a overexpression have shown to inhibit pancreatic cancer growth by reducing the STAT-3 activity levels. Chemical compounds such as thiosemicarbazone treatment in vitro and in vivo (model systems) inhibited interleukin-6 (IL-6)-induced activation of STAT-3 by the decrease in phosphorylation at Tyr705. Metformin along with aspirin doses significantly reduced the phosphorylation of STAT-3 and mechanistic target of rapamycin (mTOR). Apart from several chemicals mentioned above, there are various natural products such as genistein derivatives used as STAT-3 inhibitors. Genistein was used and tested in treatment of pancreatic, breast, and prostate cancer (PC). Genistein is shown to prevent p-STAT-3 binding to DNA in a concentration-dependent manner. Pretreatment of human pancreatic cancer cell lines such as COLO 357 and L3.6pl, by genistein for 24 h followed by gemcitabine, resulted in inhibition of growth up to 80% compared to only 30% in gemcitabine alone condition. In 2016, promising results were published from the clinical study conducted at Karolinska where patients who received genistein lived 6 months longer than their counterparts. A crystalline formulation of genistein, namely, AXP107-11, has been shown to have improved physiochemical properties and oral bioavailability in comparison to other universal forms of genistein. Pancreatic cancer (PC) patients treated with AXP107-11 along with gemcitabine resulted in improved survival. Forty-four percent of the total 16 patients in the study survived longer than 6 months, and half of them even survived longer than a year.