KISS1 in metastatic cancer research and treatment: potential and paradoxes

Ly, Thuc; Harihar, Sitaram; Welch, Danny R.

doi:10.1007/s10555-020-09868-9

Cited by 24 publications

(16 citation statements)

References 162 publications

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“…We also validated several of the top up- and downregulated genes mediated by TRIB2 overexpression in both untreated and BEZ235-treated cells ( Figure 1 D–G) by using RT-qPCR. The top genes were chosen from the list of differentially expressed genes ( Figure 1 C), from which we selected the 10 most upregulated and 10 most downregulated genes by TRIB2, as well as genes described to be involved in cancer proliferation and survival, namely Keratin 14 (KRT14), SRY-Box Transcription Factor 2 (SOX2), Formin-like protein 2 (FMNL2), BCL2-associated X, apoptosis regulator (BAX), TNF superfamily member 10 (TNFSF10), CEBPA, baculoviral IAP repeat-containing protein 7 (BIRC7), KiSS-1 metastasis suppressor (KISS1), Sestrin 2 (SESN2), MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) and BCL2 Binding Component 3 (PUMA) ( Figure 1 D–G) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. KRT14, SOX2 and FMNL2 were upregulated by TRIB2 and downregulated by BEZ235 treatment, while BAX, TNFSF10 and CEBPA were downregulated by TRIB2 ( Figure 1 D).…”

Section: Resultsmentioning

confidence: 99%

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Machado

Silva

Sousa‐Coelho

et al. 2020

Cancers

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Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.

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Section: Resultsmentioning

confidence: 99%

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Machado

Silva

Sousa‐Coelho

et al. 2020

Cancers

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“…These KISS1-mediated metabolic changes were essential for KISS1 to suppress melanoma cell invasion and metastasis ( 83 ). KISS1 functions as a metastasis suppressor gene in many cancers ( 84 ). However, KISS1R signaling in cancer appears to be context specific.…”

Section: Discussionmentioning

confidence: 99%

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Guzman¹,

Dragan²,

Kwon³

et al. 2022

Journal of Clinical Investigation

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Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

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“…Located on the long arm of chromosome 1, KISS-1 is regulated by TXNIP, CRSP3, and TCF21 and is mainly expressed in tissues such as the placenta, kidney, pancreas, and hypothalamic arcuate nucleus, where it exerts vital roles in the suppression of native tumor metastasis (161) (Figure 1). Ongoing studies confirm that the KISS-1 expression pattern significantly overlaps matrix metalloproteinases (MMP), a central mechanism by which the MMP family is involved in the metastatic process of malignant tumors, which explains the tumor metastasis inhibitory role of kisspeptin in an array of tumors (162,163). KISS-1R, the natural receptor for kisspeptin, also called Gpr54, belongs to a family of seven transmembrane G protein-coupled receptors consisting of a, b, and g subunits of which are highly distributed in the pancreas, placenta, pituitary gland, and spinal cord and similarly closely associated tumor metastasis (164,165).…”

Section: Kisspeptinmentioning

confidence: 93%

The Role of Adipokines in Pancreatic Cancer

Wang

Ding

et al. 2022

Front. Oncol.

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In modern society, inappropriate diets and other lifestyle habits have made obesity an increasingly prominent health problem. Pancreatic cancer (PC), a kind of highly aggressive malignant tumor, is known as a silent assassin and is the seventh leading cause of cancer death worldwide, pushing modern medicine beyond help. Adipokines are coming into notice because of the role of the intermediate regulatory junctions between obesity and malignancy. This review summarizes the current evidence for the relationship between highly concerning adipokines and the pathogenesis of PC. Not only are classical adipokines such as leptin and adiponectin included, but they also cover the recognized chemerin and osteopontin. Through a summary of the biological functions of these adipokines as well as their receptors, it was discovered that in addition to their basic function of stimulating the biological activity of tumors, more studies confirm that adipokines intervene in the progression of PC from the viewpoint of tumor metabolism, immune escape, and reprogramming of the tumor microenvironment (TME). Besides endocrine function, the impact of white adipose tissue (WAT)-induced chronic inflammation on PC is briefly discussed. Furthermore, the potential implication of the acknowledged endocrine behavior of brown adipose tissue (BAT) in relation to carcinogenesis is also explored. No matter the broad spectrum of obesity and the poor prognosis of PC, supplemental research is needed to unravel the detailed network of adipokines associated with PC. Exploiting profound therapeutic strategies that target adipokines and their receptors may go some way to improving the current worrying prognosis of PC patients.

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KISS1 in metastatic cancer research and treatment: potential and paradoxes

Cited by 24 publications

References 162 publications

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

The Role of Adipokines in Pancreatic Cancer

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