Adiponectin receptor agonist AdipoRon induces apoptotic cell death and suppresses proliferation in human ovarian cancer cells

Bitler, Benjamin G.; Hicks, Douglas A.; Barner, Kelsey; Qamar, Lubna; Behbakht, Kian; Powell, Theresa L.; Jansson, Thomas; Wilson, Heidi

doi:10.1007/s11010-019-03586-9

Cited by 36 publications

(33 citation statements)

References 35 publications

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“…Speci cally, ow cytometric analysis of PI-stained cells reveals a robust G0/G1 phase accumulation and S decrease in response to AdipoR treatment. Our data are fully in agreement with two recent studies in which AdipoR has been reported to have anticancer properties a ecting cell cycle distribution in a similar way [28,30]. e perfect correspondence of existing and our current ndings could suppose a precise mechanism of cell cycle control mediated by AdipoR in cancer cells; moreover, even though comprehensive experiments have never been performed, to address this hypothesis, it is important to keep in mind that even Acrp30 has been shown to mediate G1/S phase arrest in di erent cell models [38,47].…”

Section: Discussionsupporting

confidence: 93%

“…Recently, the rst oral adiponectin receptor agonist AdipoRon has been identi ed, but its potential pharmacological usage has marginally been explored [22][23][24]. In this regard, initial evidence candidates AdipoR as a potential antineoplastic molecule in various preclinical models, including pancreatic and ovarian cancer [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…e mechanistic target of rapamycin (mTOR) is a pivotal prosurvival signaling pathway that negatively affects autophagy and self-digesting independent cell death processes [41,48]. Several evidence proves that AdipoR phosphorylates the upstream mTORC1 blocker AMP-activated protein kinase (AMPK); however, the resulting impact on mTORC1 still remains unpredictable [28][29][30][42][43][44]. Our findings further confirm a not univocal and direct mTORC1 modulation mediated by AdipoR; indeed, while AdipoR causes a complete mTORC1 downstream target p70S6K inactivation in Saos-2, an unchanged trend has been detected in U2OS cells.…”

Section: Discussionmentioning

confidence: 99%

“…Adiponectin has been demonstrated to influence mTOR activity and, more specifically p70S6K, one of the best characterized downstream targets of mTOR complex-1 (mTORC1) [42][43][44]. Recently, even the aptitude of AdipoR to modulate p70S6K has also been addressed in preclinical models [30,40].…”

Section: Adipor Induces P70s6k Inactivation In Saos-2 But Not In U2osmentioning

confidence: 99%

“…Over the past few years, AdipoR is emerging as a possible candidate for the treatment of different pathological conditions, including metabolic, cardiovascular, and psychiatric disorders, specifically comorbidity between depression and obesity [22][23][24]. According to the antitumor effects observed in response to Acrp30 [25,26] and the opposite relation between its circulating levels and risk of developing cancer [27], initial reports have also investigated the possible anticancer role of AdipoRon in preclinical models, especially in pancreatic and ovarian cancer [28][29][30]. To our knowledge, no evidence has been published yet concerning the possible antiproliferative properties of AdipoR and more in general of Acrp30 in OS.…”

Section: Introductionmentioning

confidence: 99%

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AdipoRon Affects Cell Cycle Progression and Inhibits Proliferation in Human Osteosarcoma Cells

Sapio

Nigro

Ragone

et al. 2020

Journal of Oncology

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AdipoRon (AdipoR) is the first synthetic molecule acting as a selective and potent adiponectin receptor agonist. Recently, the possible pharmacological use of AdipoR in different pathological conditions has been addressed. Interestingly, initial evidence suggests that AdipoR may have anticancer properties in different preclinical models, such as pancreatic and ovarian cancer. To our knowledge, so far no research has been directed at determining the impact of AdipoR on osteosarcoma, the most aggressive and metastatic bone malignancy occurring in childhood and adolescence age. Here, we investigate the possible antitumor effects of AdipoR in osteosarcoma cell lines. MTT and cell growth curve assays clearly indicate that AdipoR inhibits, at different extents, proliferation in both U2OS and Saos-2 osteosarcoma cell lines, the latter being more sensitive. Moreover, flow cytometry-based assays point out a significant G0/G1 phase accumulation and a contemporary S phase decrease in response to AdipoR. Consistent with the different sensitivity, a strong subG1 appearance in Saos-2 after 48 and 72 hours of treatment is also observed. The investigation of the molecular mechanisms highlights a common and initial ERK1/2 activation in response to AdipoR in both Saos-2 and U2OS cells. Interestingly, a simultaneous and dramatic downregulation of p70S6K phosphorylation, one of the main targets of mTORC1 pathway, has also been observed in AdipoR-treated Saos-2, but not in U2OS cells. Importantly, a strengthening of AdipoR-induced effects was reported upon everolimus-mediated mTORC1 perturbation in U2OS cells. In conclusion, our findings provide initial evidence of AdipoR as an anticancer molecule differently affecting various signaling pathways involved in cell cycle and cell death in osteosarcoma cells and encourage the design of future studies to further understand its pattern of activities.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Adipor Induces P70s6k Inactivation In Saos-2 But Not In U2osmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AdipoRon Affects Cell Cycle Progression and Inhibits Proliferation in Human Osteosarcoma Cells

Sapio

Nigro

Ragone

et al. 2020

Journal of Oncology

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Inhibiting Wnt/beta‐catenin in CTNNB1‐mutated endometrial cancer

Moroney

Woodruff

Qamar

et al. 2021

Molecular Carcinogenesis

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The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5′-bromo-2′-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690.Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1mutant EC.

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