An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

Sulaiman, Nurfarhanah Bte Syed; Mohan, Chakrabhavi Dhananjaya; Basappa, Basappa; Pandey, Vijay; Rangappa, Shobith; Bharathkumar, Hanumantharayappa; Kumar, Alan Prem; Lobie, Peter E.; Rangappa, Kanchugarakoppal S.

doi:10.3892/ijo.2016.3615

Cited by 42 publications

(33 citation statements)

References 49 publications

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“…21 For example, Zhou et al 28 reported that miR-133b and miR-135a promoted apoptosis by JAK2/ STAT3 signaling pathway in human renal carcinoma cells. Sulaiman et al 29 revealed that an azaspirane derivative inhibited breast cancer cell growth, metastasis, invasion, and induced apoptosis by inhibiting the JAK2/STAT3 pathway. Judd et al 30 reported that JAK inhibitor WP1066 inhibited GC cell growth and reduced inflammation in vitro and in vivo by inhibiting STAT2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of long non-coding RNA HOXD-AS1 inhibits gastric cancer cell growth via inactivating the JAK2/STAT3 pathway

Chen

Zhou

et al. 2017

Tumour Biol.

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Long non-coding RNA HOXD-AS1 (HOXD cluster antisense RNA 1) has been demonstrated to be closely associated with the progression of several tumors. However, the biological function of HOXD-AS1 and the underlying molecular mechanism in gastric cancer are still unclear. The expression of HOXD-AS1 in gastric cancer cell lines was evaluated by quantitative real-time polymerase chain reaction. The association of HOXD-AS1 expression and clinical parameters was statistically analyzed by chi-square test. Cell viability, colony formation capacity, and phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 3 in treated SGC-7901 and BGC-823 cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and western blot analysis, respectively. The results indicated that HOXD-AS1 was significantly upregulated in gastric cancer cells and clinically involved in tumor size, invasion depth, tumor-node-metastasis stages, regional lymph nodes, lymphatic metastasis, as well as distant metastasis. HOXD-AS1 knockdown dramatically inhibited gastric cancer cell proliferation, colony formation capacity, and phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 3 in vitro. In addition, HOXD-AS1 overexpression significantly promoted gastric cancer cell proliferation and colony formation capacity, whereas both Janus kinase small interfering RNAs and Janus kinase 2 inhibitor AG490 overturned these effects. Furthermore, xenograft assays confirmed the biological function of HOXD-AS1 in vivo. Taken together, our data elucidate that knockdown of HOXD-AS1 dramatically suppresses gastric cancer cell growth by inactivating the Janus kinase 2/signal transducer and activator of transcription 3 pathway in vitro and in vivo, contributing to a better understanding of gastric cancer pathogenesis and providing a possible theoretical foundation for long non-coding RNA-directed diagnosis and therapy against this disease.

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Section: Discussionmentioning

confidence: 99%

Knockdown of long non-coding RNA HOXD-AS1 inhibits gastric cancer cell growth via inactivating the JAK2/STAT3 pathway

Chen

Zhou

et al. 2017

Tumour Biol.

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“…In addition to phase I/II trials of atiprimod alone, studies about atiprimod combined treatment with various proteasomal inhibitors such as bortezomib in multiple myeloma and mantle cell lymphoma in vitro and in vivo have also been reported . Atiprimod prevents hepatocellular carcinoma and breast cancer cell proliferation and triggers mitochondrial membrane potential loss and nuclear condensation . The major target molecule in atiprimod induced apoptotic cell death depends on the suppressive effect on STAT‐3 molecule in hepatocellular carcinoma and breast cancer cells …”

Section: Introductionmentioning

confidence: 99%

Atiprimod induce apoptosis in pituitary adenoma: Endoplasmic reticulum stress and autophagy pathways

Gürkan

Ayhan-Sahin

Keceloglu

et al. 2019

J of Cellular Biochemistry

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Pituitary adenoma is the most common tumor with a high recurrence rate due to a hormone-dependent JAK/signal transducer and activator of transcriptions (STAT) signaling. Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, has antiproliferative, anticarcinogenic effects in multiple myeloma, breast, and hepatocellular carcinoma by blocking STAT3 activation. Therapeutic agents' efficiency depends on endoplasmic reticulum (ER) stress-autophagy regulation during drug-mediated apoptotic cell death decision. However, the molecular machinery of dose-dependent atiprimod treatment regarding ER stress-autophagy has not been investigated yet. Thus, our aim is to investigate the ER stress-autophagy axis in atiprimodmediated apoptotic cell death in GH-secreting rat cell line (GH3) pituitary adenoma cells. Dose-dependent atiprimod treatment decreased GH3 cell viability, inhibited cell growth, and colony formation. Upregulation of Atg5, Atg12, Beclin-1 expressions, cleavage of LC-3II and formation of autophagy vacuoles were determined only after 1 µM atiprimod exposure. In addition, atiprimod-triggered ER stress was evaluated by BiP, C/EBP-homologous protein (CHOP), p-PERK upregulation, and Ca +2 release after 1 µM atiprimod exposure.Concomitantly, increasing concentration of atiprimod induced caspase-dependent apoptotic cell death via modulating Bcl 2 family members. Moreover, by Nacetyl cycteinc pretreatment, atiprimod triggered reactive oxygen species generation and prevented apoptotic induction. Concomitantly, dose-dependent atiprimod treatment decreased both GH and STAT3 expression in GH3 cells. In Abbreviations: AMPK, AMP-activated protein kinase; AO, acridine orange; ATF6, activating transcription factor 6; CHOP, C/EBP-homologous protein; DiOC6, 3,3′-dihexyloxacarbocyanine iodide; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; eIF-2 α, eukaryotic initiation factor 2; HRP, horseradish peroxidase; IRE-1α, inositol-requiring protein-1α; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-

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“…JAK2 is reported to be a upstream regulator of STAT3 [ 16 ]. Thus, we investigated the regulatory effects of miR-216a on activation of JAK2/STAT3 pathway in GC cells.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-216a inhibits the metastasis of gastric cancer cells by targeting JAK2/STAT3-mediated EMT process

Tao

Yang

et al. 2017

Oncotarget

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MicroRNAs (miRNAs), a group of small, non-protein coding, endogenous RNAs, play critical roles in the tumorigenesis and progression of human cancer. miR-216a has recently been reported to play an oncogenic role in human cancer. While, the expression of miR-216a, its biological function and underlying molecular mechanisms in gastric cancer (GC) are largely unknown. In this study, we revealed that miR-216a was underexpressed in GC tissues compared to matched noncancerous tissues. Decreased levels of miR-216a were confirmed in GC cell lines compared with a normal gastric epithelium cell line. miR-216a underexpression was associated with malignant prognostic features including lymph node metastasis, venous infiltration, invasive depth and advanced TNM stage. GC patients with low miR-216a level showed an obvious shorter overall survival. miR-216a overexpression restrained migration and invasion of MGC-803 cells, while its knockdown exerted opposite effects on metastatic behaviors of SGC-7901 cells. In vivo experiments found that miR-216a restoration reduced metastatic nodes of GC cells in nude mice liver. miR-216a notably suppressed epithelial-mesenchymal transition (EMT) of GC cells. Janus kinase 2 (JAK2) was recognized as a direct target and downstream mediator of miR-216a in GC cells. Interestingly, JAK2/signal transducer and activator of transcription 3 (STAT3) pathway was prominently inactivated by miR-216a and probably mediated the role of miR-216a in the regulation of migration, invasion and EMT process of GC cells. In conclusion, these data suggest that miR-216a functions as a tumor suppressive miRNA in the development of GC possibly by targeting JAK2/STAT3-mediated EMT.

show abstract

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

Cited by 42 publications

References 49 publications

Knockdown of long non-coding RNA HOXD-AS1 inhibits gastric cancer cell growth via inactivating the JAK2/STAT3 pathway

Knockdown of long non-coding RNA HOXD-AS1 inhibits gastric cancer cell growth via inactivating the JAK2/STAT3 pathway

Atiprimod induce apoptosis in pituitary adenoma: Endoplasmic reticulum stress and autophagy pathways

MicroRNA-216a inhibits the metastasis of gastric cancer cells by targeting JAK2/STAT3-mediated EMT process

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