Introduction
Lung cancer contributes largely to cancer-related mortality worldwide (Huang et al., 2016; Lee, Kim, Sethi & Ahn, 2015; Mason, 1949; Siegel, Miller & Jemal, 2015). Human lung cancer consists of non-small lung cancer (NSCLC) and small cell lung cancer (SCLC) (Zhang et al., 2016; Zhu et al., 2018). NSCLC is more common form and five-year survival rate is generally less than 5% in advanced cases (Lee et al., 2019a; Reck, Heigener, Mok, Soria & Rabe, 2013; Wang et al., 2018; Yang, Lee, Ko, Jung, Sethi & Ahn, 2019). Surgery operation, radiation therapy, chemotherapy, targeted therapy etc are are routinely used for management of NSCLC patients (Lee, Chinnathambi, Alharbi, Shair, Sethi & Ahn, 2019; Lee, Kim, Lee, Sethi & Ahn, 2018b; Yang et al., 2005). However, these traditional treatment modalities may be associated with low specificity and serious side effects on patients (Artal Cortes, Calera Urquizu & Hernando Cubero, 2015; Ko, Nam, Um, Jung, Sethi & Ahn, 2018; Lee et al., 2018; Liu, Kuang, Wu, Jin & Sun, 2016). Hence, the evolution of novel agents for the NSCLC therapy are still required.
Signal transducer and activators of transcription (STAT) family is made up of STAT1, STAT2, STAT3, STAT4, STAT5α, STAT5β, and STAT6 (Ashrafizadeh et al., 2019; Loh, Arya, Naema, Wong, Sethi & Looi, 2019; Mohan et al., 2020; Schindler, Levy & Decker, 2007; Wong, Hirpara, Pervaiz, Eu, Sethi & Goh, 2017; Yu, Pardoll & Jove, 2009). Among these proteins, STAT3 activated has been found to be deregulated in varied human cancer cells, such as head and neck, lung, breast, prostate, kidney, pancreas, liver cancer lymphomas, multiple myeloma (Arora, Kumar, Arfuso, Chng & Sethi, 2018; Hwang et al., 2019; Kim et al., 2014; Lee et al., 2014; Lee, Kim, Lee, Um, Sethi & Ahn, 2019; Lee et al., 2019b; Loh, Arya, Naema, Wong, Sethi & Looi, 2019; Yang et al., 2019). STAT3 can regulate varying hallmarks of cancer and promote expression of various tumorigenic genes (Baek et al., 2017; Kim et al., 2018; Lee et al., 2017; Lee, Kim, Kim, Sethi & Ahn, 2015; Shanmugam et al., 2015). The activation of STAT3 can be mediated by upstream kinases (JAK1/2 and Src) and undergo dimerization, translocation into nucleus, DNA binding, thus promoting transcription (Baek et al., 2016a; Fathi, Rashidi, Khodadadi, Shahi & Sharifi, 2018; Lee, Kim, Lee, Sethi & Ahn, 2018a; Wang & Sun, 2014). In addition, diverse protein tyrosine phosphatases (PTPs) such as SHP-1, SHP-2, PTEN, and PTPε can also control STAT3 pathway. PTPε occurs in both transmembrane (PTPε M) and cytosolic (PTPε C) forms (Nakamura, Mizuno & Kikuchi, 1996; Yang et al., 2019). PTPε M can be expressed in brain, testis, and lung, whereas PTPε C is expressed in spleen thymus, and peritoneal macrophages (Elson & Leder, 1995; Tanuma, Nakamura & Kikuchi, 1999; Tanuma, Shima, Nakamura & Kikuchi, 2001). Interestingly, PTPε C was found to abrogate IL-6-stimulated JAK/STAT casacde in murine leukemia cells (Tanuma, Nakamura, Shima & Kikuchi, 2000).
Natural products remain the mainstay for discovery of novel anti-cancer drugs (Dai et al., 2015; Shanmugam, Warrier, Kumar, Sethi & Arfuso, 2017; Siveen et al., 2014; Tewari et al., 2018; Zhou et al., 2020). Ginkgo biloba(Ginkgoaceae) is one of the common ancient trees, and has been used as a medical herb for a long time in clinical therapy in oriental and western medicine (Yeh, Shou, Lin, Chen, Chiang & Yeh, 2015). Ginkgolide C (GGC) isolated from Ginkgo bilobaleaves, is a flavone with multiple biological functions (Huang et al., 2014; Huang, Chen, Liu, Wu & Liou, 2018; Liou, Lai, Chen, Wang, Wei & Huang, 2015; Zhang et al., 2018). GGC has been implicated to increase lipolysis and suppress adipogenesis in 3T3-L1 adipocyte through modulation of AMPK signaling cascades (Liou, Lai, Chen, Wang, Wei & Huang, 2015). In addition, GGC can alleviate myocardial ischemia/reperfusion injury through suppression of CD40-NF-kB signaling pathway (Zhang et al., 2018). GGC also has been reported to reduce oleic acid-induced lipid accumulation via the Sirt1/AMPK pathway (Huang, Chen, Liu, Wu & Liou, 2018). However, up to now, there is little research on the impact of GGC on the progression of human cancers. STAT3 has been implicated to regulate tumorigeensis (Dai et al., 2016; Li et al., 2013), it may be possible that GGC may exert its anti-cancer actions through affecting this pathway.
In this study, we investigated whether GGC induce apoptosis and affect NSCLC growth by modifying the activation of STAT3 pathway. We noted that GGC can mitigate STAT3 activation by affecting PTPε tyrosine phosphatase in NSCLC cells that mediates its anti-oncogenic impact. Thus, GGC can act as a potent blocker of STAT3 signaling pathway and abrogate tumor growth effectively in NSCLC model.