1 INTRODUCTION
Pancreatic cancer is a highly lethal malignancy, which is characterized
by the close parallel between cancer incidence and death rates,
asymptomatic development, and an extremely poor prognosis (Kleeff et
al., 2016; Aier, Semwal, Sharma, & Varadwaj, 2019). According to global
cancer statistics, pancreatic cancer is the seventh leading cause of
cancer-associated mortality worldwide in 2018 (Bray et al., 2018). Due
to the rapid cancer progression without specific symptoms, most patients
with pancreatic cancer are diagnosed at advanced stages. The 5-year
relative survival rate in patients diagnosed with the disease remains as
low as 9% in the United States (Siegel, Miller, & Jemal, 2020).
Therefore, pancreatic cancer is commonly fatal. Pancreatic cancer is
predicted to become the second leading death cause from cancer in the
United States by 2030 (Rahib et al., 2014). However, over the past few
decades, therapeutic drugs for pancreatic cancer have yielded very
limited success in clinical trials (Roth, Cardin, & Berlin, 2020;
Kamisawa, Wood, Itoi, & Takaori, 2016). Moreover, drug resistance is a
serious problem in the treatment of pancreatic cancer (Binenbaum,
Na’ara, & Gil, 2015). Thus, development of effective targeted agents
for treating pancreatic cancer is urgently needed.
STAT3 is a pro-oncogenic transcription factor, and is regarded as a
therapeutic target in numerous human cancers, including lung cancer,
colorectal cancer, breast cancer, prostate cancer, ovarian cancer and so
on (Dutta, Sabri, Li, & Li, 2015; Banerjee & Resat, 2016; Ouédraogo et
al., 2017; Liang et al., 2020). STAT3 regulates the expression of its
downstream target genes related to cell proliferation, survival,
migration, invasion, epithelial-mesenchymal transition, tumor
angiogenesis, the Warburg effect, cancer stem cell properties, and
immune evasion closely connected with cancer progression and malignancy
(Carpenter & Lo, 2014; Kamran, Patil, & Gude, 2013; Wendt, Balanis,
Carlin, & Schiemann, 2014; Gao et al., 2017; Demaria et al., 2010;
Galoczova, Coates, & Vojtesek, 2018; Wang et al., 2004). Persistently
activated STAT3 also mediates cancer-associated inflammation that can
initiate and promote malignant transformation, and genetic alterations
in pre-neoplastic and malignant cells can also induce and maintain a
tumor-promoting inflammatory microenvironment that further facilitates
tumorigenesis and malignant progression (Fan, Mao, & Yang, 2013; Yu,
Lee, Herrmann, Buettner, & Jove, 2014; Yu, Pardoll, & Jove, 2009). In
addition to the tumor cells, STAT3, which is a converging point of
numerous oncogenic pathways, is also constitutively activated in
tumor-infiltrated immune cells, resulting in suppression of immune
mediators and promotion of immunosuppressive factors (Wang, Shen, Wang,
Shen, & Zhou, 2018; Yu, Kortylewski, & Pardoll, 2007). In addition,
accumulating evidence also indicates that feedback activation of STAT3
plays a critical role in mediating the drug resistance that often
follows the targeted cancer therapies and conventional chemotherapies
(Lee et al., 2017; Zhao et al., 2016). Taken together, inhibiting STAT3
activation is an attractive and promising approach for cancer
prevention, therapy and drug sensitization (Johnson, O’Keefe, &
Grandis, 2018; Furtek, Backos, Matheson, & Reigan, 2016).
Overexpression and hyperactivation of the oncoprotein STAT3 frequently
occur in pancreatic cancer (Scholz et al., 2003; Fofaria & Srivastava,
2015; He et al., 2018; Wei et al., 2003). STAT3 is also a major mediator
in KRAS -driven pancreatic cancer that lacks clinically actionable
targets (Li, Grivennikov, & Karin, 2011; D’Amico et al., 2018). Hence,
inhibiting aberrantly activated STAT3 is a promising strategy for
pancreatic cancer therapy.
To identify natural compounds that block the transcriptional activity of
STAT3, we utilized the STAT3-luciferase (STAT3-luc) reporter system
containing STAT3-binding elements to screen potentially active compounds
from our in-house natural product library including more than 1000
compounds and identified a natural compound termed Trienomycin A (TA), a
secondary metabolite produced by the moss-soil-derived actinomyceteStreptomyces cacaoi subsp. asoensis H2S5, that has
anti-neuroinflammatory and anti-tumor activities (Tang et al., 2018; Liu
et al., 2020). However, very little is known about the impact of TA on
pancreatic cancer, and the underlying molecular mechanisms of TA are
also unclear. In this study, we found that TA memorably repressed the
transcriptional activity of STAT3. We further demonstrated TA inhibited
the phosphorylation of tyrosine at the 705 site of STAT3 and the protein
expression of downstream target genes that related to cell
proliferation, growth, migration and invasion, by binding to STAT3
protein. Furthermore, we found that TA significantly reduced the growth
of pancreatic tumor in vivo , and that TA had no obvious toxic
effects on the normal tissues (heart, liver, spleen, lung and kidney) of
mice. Collectively, our data give the first evidence that TA is a
potential STAT3 pathway inhibitor with significant activity against
pancreatic cancer, and it is worthwhile to be further studied.