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2. Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes.

Author

Kulkarni, Prateek, Basu, Reetobrata, Bonn, Taylor, Low, Beckham, Mazurek, Nathaniel, and Kopchick, John J.

Subjects
*PROTEIN metabolism, *MELANOMA, *SKIN tumors, *DRUG resistance in cancer cells, *PHENOMENOLOGICAL biology, *RESEARCH funding, *ANTINEOPLASTIC agents, *CELL motility, *BIOCHEMISTRY, *DESCRIPTIVE statistics, *CANCER chemotherapy, *ONCOLOGY nursing, *CELL culture, *CELL lines, *METASTASIS, *PROTEOLYTIC enzymes, *DOXORUBICIN, *HUMAN growth hormone, *EXOSOMES
Abstract

Simple Summary: Melanoma, a severe type of skin cancer, often becomes resistant to chemotherapy, making it difficult to treat. This research investigates a novel mechanism by which growth hormone (GH) contributes to chemotherapy resistance. We examined small particles, called exosomes, which are released from melanoma cells treated with GH and found to carry proteins that increase drug resistance and cancer cell movement. The effects were more pronounced when GH was combined with the chemotherapy drug, doxorubicin. We also found that blocking the GH action with a drug called pegvisomant reduced the expression of these exosomal proteins, ultimately making the cancer cells more responsive to chemotherapy and less likely to migrate. Our findings provide new insights into how GH action promotes melanoma chemoresistance via exosomes, suggesting that targeting/inhibiting GH action could improve melanoma treatment. Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.

Author

Basu, Reetobrata, Kulkarni, Prateek, Swegan, Deborah, Duran-Ortiz, Silvana, Ahmad, Arshad, Caggiano, Lydia J., Davis, Emily, Walsh, Christopher, Brenya, Edward, Koshal, Adeel, Brody, Rich, Sandbhor, Uday, Neggers, Sebastian J. C. M. M., and Kopchick, John J.

Subjects
*SOMATOTROPIN receptors, *PITUITARY dwarfism, *HORMONE antagonists, *PANCREATIC cancer, *TREATMENT effectiveness, *LABORATORY mice, *GEMCITABINE
Abstract

Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)–GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

Author

Basu, Reetobrata, primary, Qian, Yanrong, additional, Mathes, Samuel, additional, Terry, Joseph, additional, Arnett, Nathan, additional, Riddell, Trent, additional, Stevens, Austin, additional, Funk, Kevin, additional, Bell, Stephen, additional, Bokal, Zac, additional, Batten, Courtney, additional, Smith, Cole, additional, Mendez-Gibson, Isaac, additional, Duran-Ortiz, Silvana, additional, Lach, Grace, additional, Mora-Criollo, Patricia Alexandra, additional, Kulkarni, Prateek, additional, Davis, Emily, additional, Teaford, Elizabeth, additional, Berryman, Darlene E., additional, List, Edward O., additional, Neggers, Sebastian, additional, and Kopchick, John J., additional

Published
2022
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12. Growth hormone receptor gene disruption in mature‐adult mice improves male insulin sensitivity and extends female lifespan

Author

Duran‐Ortiz, Silvana, primary, List, Edward O., additional, Ikeno, Yuji, additional, Young, Jonathan, additional, Basu, Reetobrata, additional, Bell, Stephen, additional, McHugh, Todd, additional, Funk, Kevin, additional, Mathes, Samuel, additional, Qian, Yanrong, additional, Kulkarni, Prateek, additional, Yakar, Shoshana, additional, Berryman, Darlene E., additional, and Kopchick, John J., additional

Published
2021
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14. Antagonism of Growth Hormone Receptor Suppresses Cancer Growth and Drug Resistance in Mice

Author

Qian, Yanrong, primary, Basu, Reetobrata, additional, Terry, Joseph, additional, Mathes, Samuel Casey, additional, Arnett, Nathan, additional, Smith, Cole, additional, Mendez-Gibson, Isaac, additional, Brittain, Alison, additional, Ortiz, Silvana Duran, additional, Kulkarni, Prateek, additional, Funk, Kevin Ray, additional, Bell, Stephen Robert Clyde, additional, List, Edward Owen, additional, Berryman, Darlene E, additional, and Kopchick, John Joseph, additional

Published
2021
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17. A Simpler Proof of The Collatz Conjecture

Author

Kulkarni, Prateek P

Subjects
Mathematics::General Mathematics, Physics::Chemical Physics, Physics::Classical Physics, Nonlinear Sciences::Cellular Automata and Lattice Gases, Physics::Geophysics
Abstract

The author provides a simple proof of Collatz Conjecture, using at disposal elementary mathematics.

Published
2020
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18. A Proof of the Collatz Conjecture

Author

Kulkarni, Prateek P

Subjects
Mathematics::General Mathematics, Nonlinear Sciences::Cellular Automata and Lattice Gases, Physics::History of Physics
Abstract

The author provides a proof of the infamous Collatz Conjecture.

Published
2020
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19. Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo

Author

Qian, Yanrong, primary, Basu, Reetobrata, additional, Mathes, Samuel C., additional, Arnett, Nathan A., additional, Duran-Ortiz, Silvana, additional, Funk, Kevin R., additional, Brittain, Alison L., additional, Kulkarni, Prateek, additional, Terry, Joseph C., additional, Davis, Emily, additional, Singerman, Jordyn T., additional, Henry, Brooke E., additional, List, Edward O., additional, Berryman, Darlene E., additional, and Kopchick, John J., additional

Published
2020
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20. The Effects of 20-kDa Human Placental GH in Male and Female GH-deficient Mice: An Improved Human GH?

Author

List, Edward O, primary, Berryman, Darlene E, additional, Basu, Reetobrata, additional, Buchman, Mathew, additional, Funk, Kevin, additional, Kulkarni, Prateek, additional, Duran-Ortiz, Silvana, additional, Qian, Yanrong, additional, Jensen, Elizabeth A, additional, Young, Jonathan A, additional, Yildirim, Gozde, additional, Yakar, Shoshana, additional, and Kopchick, John J, additional

Published
2020
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21. Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

Author

Basu, Reetobrata, primary, Kulkarni, Prateek, additional, Qian, Yanrong, additional, Walsh, Christopher, additional, Arora, Pranay, additional, Davis, Emily, additional, Duran-Ortiz, Silvana, additional, Funk, Kevin, additional, Ibarra, Diego, additional, Kruse, Colin, additional, Mathes, Samuel, additional, McHugh, Todd, additional, Brittain, Alison, additional, Berryman, Darlene E., additional, List, Edward O., additional, Okada, Shigeru, additional, and Kopchick, John J., additional

Published
2019
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