Inferring the Effects of Honokiol on the Notch Signaling Pathway in SW480 Colon Cancer Cells

Abstract

In a tumor cell, the development of acquired therapeutic resistance and the ability to survive in extracellular environments that differ from the primary site are the result of molecular adaptations in potentially highly plastic molecular networks. The accurate prediction of intracellular networks in a tumor remains a difficult problem in cancer informatics. In order to make truly rational patient-driven therapeutic decisions, it will be critical to develop methodologies that can accurately infer the molecular circuitry in the cells of a specific tumor. Despite enormous heterogeneity, cellular networks elicit deterministic digital-like responses. We discuss the use and limitations of methodologies that model molecular networks in cancer cells as a digital circuit. We also develop a network model of Notch signaling in colon cancer using a novel reverse engineering logic-based method and published western blot data to elucidate the interactions likely present in the circuits of the SW480 colon cancer cell line. Within this framework, we make predictions related to the role that honokiol may be playing as an anti-cancer drug.

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…In addition, there were reduced levels of DCLK1 and the Notch signalling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signalling pathway [35,204].…”

“…It was shown that honokiol enhanced the sensitization of GBM cells to MGMT inhibitor O6 benzylguanine (O6-BG) through the downregulation of Notch3 as well as the expression of its downstream target, Hes1 [36]. Furthermore, honokiol has been shown to inhibit B16/F-10, SKMEL-28 melanoma cell lines and SW480 colon cancer cells by targeting Notch signalling pathways [203,204]. Honokiol treatment resulted in reduced levels of cleaved Notch, particularly the Notch-2 receptor, along with a decrease in the expression of downstream target proteins, including Hes-1, cyclin D1, as well as TACE and γ-secretase complex proteins in melanoma cells [55].…”

“…Apart from that, honokiol in combination with radiation treatment reduced the number of DCLK1+ (cancer stem cell marker protein) colon cancer cells, which was accompanied by reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1 [35,204]. Furthermore, the expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 were also suppressed [35].…”

BMP7 mediates the anticancer effect of honokiol by upregulating p53 in HCT116 cells

“…HNK may exerts such activities through various signaling pathways and molecules, such as STAT3, epidermal growth factor receptor (EGFR), nuclear factor-κB (NF-κB), cell survival signaling, cell cycle, and inflammatory mediators (10)(11)(12)(13). It has been reported that HNK shows anticancer activities in CRC (14)(15)(16), but the explicit mechanism under this effect remains unclear.…”

Predicting neuroblastoma using developmental signals and a logic-based model

“…For example, Wynn and colleagues (19) develop a network model of Notch signaling in colon cancer using a novel reverse engineering Boolean-based method and discover potential mechanisms of actin for honokiol as an anti-cancer drug. Boolean models are also specifically suited to capturing the qualitative features of interacting components, such as T cell receptor signaling, cell cycle transition between the G1/S phases and hepatocellular specification (20–23).…”