KISS1 in metastatic cancer research and treatment: potential and paradoxes
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NON-THEMATIC REVIEW
KISS1 in metastatic cancer research and treatment: potential and paradoxes Thuc Ly 1
&
Sitaram Harihar 2
&
Danny R. Welch 1,3
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized. Keywords Metastasis . Metastasis suppressor . KISS1 . KISS1R . Dormancy . G protein-coupled receptor
Abbreviations DAG Diacylglycerol E2 Estrogen ER Estrogen receptor ERK Extracellular signal-regulated kinase FSH Follicle-stimulating hormone GPCR G protein-coupled receptor IP3 Inositol trisphosphate LH Luteinizing hormone MAPK Mitogen activate protein kinase PI3K Phosphatidylinositol 3-kinase PIP2 Phosphatidylinositol (4,5)-bisphosphate PLC Phospholipase C
* Danny R. Welch [email protected] Thuc Ly [email protected] Sitaram Harihar [email protected] 1
Department of Cancer Biology, Kansas University Medical Center, 3901 Rainbow Blvd. - MS1071, Kansas City, KS 66160, USA
2
Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
3
University of Kansas Cancer Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
SNP TNBC
Single-nucleotide polymorphism Triple-negative breast cancer
1 Introduction 1.1 Why care about KISS1? KISS1 was discovered as a metastasis suppressor in melanoma following microcell-mediated introduction of whole, wildtype chromosome 6 into metastatic melanoma cells followed by subtractive hybridization comparing cells suppressed for metastasis [1]. Early studies identified that KISS1 was highly expressed in the placenta and brain, with lesser expression in the kidney and pancreas, and negligible expression in other tissues [1–4]. Since invasion of trophoblasts during pregnancy resembles tumor invasion, early speculation was that KISS1 inhibits invasion as the explanation for metastasis suppression. While invasion was inhibited in the majority of cancer cell lines tested, the blockage was not complete, and since metastasis only requires some ability to invade (i.e., even weakly invasive cells can metastasize as long as those cells retain the ability to complete the other steps of the metastatic cascade), other processes were thought to be more relevant. Regardless, the ca
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