JNK pathway inhibition selectively primes pancreatic cancer stem cells to TRAIL-induced apoptosis without affecting the physiology of normal tissue resident stem cells

Abstract

ABSTRACT

Elaeagnus angustifolia Plant Extract Inhibits Epithelial-Mesenchymal Transition and Induces Apoptosis via HER2 Inactivation and JNK Pathway in HER2-Positive Breast Cancer Cells

“…The JNK pathway is predominantly involved in the stimulation of the intrinsic apoptotic pathway facilitated by mitochondria [ 61 ]. However, the JNK pathway is also involved in TRAIL-induced apoptosis, autophagy, mitotic catastrophe, and immunogenic cell death [ 62 , 63 , 64 , 65 , 66 ]. Our data show upregulation of Bax and capsase-3 expression and downregulation of Bcl-2, indicating that apoptosis occurs via the extrinsic pathway as well [ 65 ]; a loss of JNK could primarily trigger extrinsic apoptosis.…”

“…However, the JNK pathway is also involved in TRAIL-induced apoptosis, autophagy, mitotic catastrophe, and immunogenic cell death [ 62 , 63 , 64 , 65 , 66 ]. Our data show upregulation of Bax and capsase-3 expression and downregulation of Bcl-2, indicating that apoptosis occurs via the extrinsic pathway as well [ 65 ]; a loss of JNK could primarily trigger extrinsic apoptosis. Moreover, Bax/Bcl-2/caspase-3 is also involved in other types of regulated cell death, including immunogenic cell death, mitotic catastrophe, and mitochondrial permeability transition (MPT)-driven necrosis [ 67 ], thus suggesting JNK inhibition to mediate Bax/Bcl-2/caspase-3 apoptosis.…”

Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy

“…Evaluation of JNK-IN-8 in PDAC is still limited to well-characterized cell lines, and JNK-IN-8 has not been studied in combination with chemotherapies (30). Therefore, we assessed the therapeutic potential of JNK-IN-8 in combination with FOLFOX and its components in vitro with 72-hour 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays across a wide range of constant-ratio dose combinations ( Figure 3A), as well as with longer-term 14-day colony formation assays dosed with drugs every 3 days and visualized by crystal violet stain ( Figure 3B).…”

“…JNK possesses similarly multifaceted roles in PDAC, with verified tumor-suppressive (23,24) and tumor-promoting functions (25)(26)(27) that may be dependent upon a number of factors, including the stage of tumor initiation/development being assessed and whether JNK is being studied in the context of another treatment. JUN has been found to be overexpressed in PDAC (28), prompting testing of JNK inhibition as a therapeutic approach in PDAC (25,29,30), but most of these studies have relied upon the reversible inhibitor SP600125 that has been proven to be highly nonspecific. SP600125 inhibits a wide range of kinases, including p38, CDK1, and MEK/ERK -all pathways with connections to JNK signaling that could be confounding (31)(32)(33).…”

Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs)

“…Accordingly, applying these markers to target CSCs is challenging due to their low specificity and lack of potential efficacy. CSC signaling activity or overactivation of pathways such as Wnt/RSPO (R-spondin) [ 27 ], c-Jun N-terminal protein kinase (JNK) [ 28 ], Nodal/Activin [ 29 ], Notch [ 30 ] or Hedgehog [ 24 ] as well as adaptability of CSCs to the ever-changing tumor microenvironment and CSC niche [ 31 , 32 , 33 ] are further critical components of the CSC concept.…”