Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling

Abstract

PurposeThe chemical structure of tubulosine has been known since the mid-1960s. However, little is known about its biological and pharmacological functions. The aim of this study was to investigate the novel functions of tubulosine in cancer treatment, specifically in breast cancer.MethodsAn Unpaired (Upd)-induced Drosophila cell line and interleukin (IL)-6-stimulated human breast cancer cell lines were used to investigate the biological and pharmacological activities of tubulosine in vitro. To investigate the activities of tubulosine, we performed molecular and cellular experiments such as Western blot and reverse transcription polymerase chain reaction analyses, immunoprecipitation and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunofluorescence staining using breast cancer cell lines.ResultsTubulosine exhibited anticancer activity in IL-6-stimulated human breast cancer cells. Moreover, tubulosine reduced the tyrosine phosphorylation level and transcriptional activity of signal transducer and activator of transcription (STAT) protein at 92E in Upd-induced Drosophila cells. Additionally, tubulosine suppressed IL-6-induced Janus kinase 2 (JAK2)/STAT3 signaling, resulting in decreased viability and induction of apoptotic cell death in breast cancer cells. Interestingly, inhibition of IL-6-induced JAK2/STAT3 signaling by tubulosine was associated with the blocking of IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) binding.ConclusionTubulosine exhibits anticancer activity through functional inhibition of IL-6-induced JAK2/STAT3 signaling by targeting IL-6Rα/gp130 binding in breast cancer cells. These findings suggest that tubulosine may hold promise for the treatment of inflammation-associated cancers, including breast cancer.

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

“…These cases of cancer are responsible for the difficulty in treating and important factors in determining the prognosis of breast cancer patients [9]. Specifically, higher level of tyrosine phosphorylated STAT3 was observed in TNBC subtype of breast cancer cells than those of other subtypes [15,16,17,18].…”

“…In fact, STAT3 is persistently activated in more than 40% of breast cancer patients. Particularly, high level of activated STAT3 is observed in TNBC subtype, which is closely related to the promotion of cancer progression and metastasis, increased resistance to chemotherapy, and reduced overall survival rates in cancer patients [15,16,17,18]. Putting these evidences together, STAT3 is an important therapeutic target for cancer treatment.…”

IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment

“…Aryappalli and colleagues report Manuka honey antagonizes IL-6Rα which inhibits downstream gp130, pJAK2, and pSTAT3; Manuka honey flavonoids, luteolin, chrysin, quercetin, and galangin disrupt IL-6 binding to IL-6Rα ( 141 ). Investigation of anti-cancer mechanisms of tubulosine, originally isolated from bark of Pogonopus tubulosus in 1964, identified tubulosine as a potent inhibitor of JAK2/STAT3 signaling through disruption of IL-6/IL-6Rα/gp130 complex formation ( 142 ). Furthermore, a triterpenoid saponin extracted from traditional Chinese medicine, Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), exhibits immunomodulatory effects by directly binding and antagonizing IL-6Rα.…”

Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer

“…Therefore, in the current study, a large library of plant-derived natural compounds was subjected to the SBDD approach for the selection of potent inhibitors against 6-PGD, which identified five potential candidates, including secoisolariciresinol, syringaresinol, cleomiscosin A, tubulosine and terrestriamide, with a free binding energy range of −26.086 to −18.455 kcal/mol. According to the literature, these compounds have been reported to hold several bioactivities, such as tubulosine, which has been attributed as an anticancer and antiplasmodic agent [ 44 , 45 ], terresriamide as an hepatoprotective and antinitric oxide production activity compound [ 46 , 47 ], secoisolariciresinol and syringaresinol as good antioxidant and antimicrobial agents [ 48 , 49 , 50 , 51 ], and cleomiscosin A as an antioxidant as well as vasorelaxant for rat aortic ring [ 52 , 53 ].…”