Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
- Cell culture and treatments: The human melanoma cell lines, MALME-3M (HTB-64) and SK-MEL-28 (HTB-72), were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA), while the SK-MEL-30 cell line was acquired from Creative Bioarray (Shirley, NY, USA). Cells were grown and maintained in Iscove’s Modified Dulbecco’s Medium (IMDM), Eagle’s Minimum Essential Medium (EMEM), and Rosewell Park Memorial Institute (RPMI) media, respectively, supplemented with 10% fetal bovine serum (# 10-082-147, Thermo Fisher Scientific, Waltham, MA) and 100 U/mL penicillin–streptomycin (#15-140-22, Thermo Fisher Scientific, Waltham, MA, USA). Cells were grown in a humidified incubator at 37 °C and 5% CO2. Recombinant human GH (#ABIN2017921, Antibodies-online, Pottstown, PA, USA) at 50 ng/mL, doxorubicin at the EC50 dosage, and pegvisomant (Somavert, Pfizer) at 500 nM were added in the respective treatment media supplemented with 2% exosome-depleted fetal bovine serum (#EXO-FBS-250A-1, System Biosciences, Palo Alto, CA, USA). We confirmed that GH promoted and the GHR antagonist, pegvisomant, attenuated phosphorylation levels of STAT5 in the aforementioned treatment combinations in all the three melanoma cell lines (Supplementary Figure S1). The EC50 values were determined as 0.7 µM for Malme-3M, 1.5 µM for SK-MEL-28, and 2.8 µM for SK-MEL-30 (Supplementary Figure S2). The melanoma cells were treated with doxorubicin at the EC50 dosage for 96 h, with replacement every 48 h.
- Exosome isolation: The supernatants of the cell cultures from the respective treatments were centrifuged at 3000× g for 15 min at 4 °C to remove the cell debris. Further, the supernatant was passed through the 0.22 µm filter (Millipore Sigma, Burlington, MA, USA) to remove the relatively large vesicles. To effectively concentrate exosomes from large volumes, ultrafiltration was employed using Amicon Ultra 15 mL centrifugal filters (100 kDa NMWL, Millipore Sigma, Burlington, MA, USA) [43]. Next, the ExoQuick reagent was added to the supernatant in 1:5 ratio, according to the manufacturer’s instructions (Systems Biosciences, Palo Alto, CA, USA) and incubated overnight at 4 °C with no rotation. Following incubation, the samples were centrifuged at 1500× g for 30 min. The supernatant was aspirated, followed by a brief centrifugation step of 1500× g for 5 min to facilitate further removal of the supernatant. The final pellet was resuspended in phosphate-buffered saline (PBS) for the downstream analysis.
- Nanoparticle tracking analysis: Exosome labeling was conducted using the EV tracker green NTA labeling kit (Systems Biosciences, Palo Alto, CA, USA). Briefly, the pre-warmed reaction buffer was mixed with ExoGlowTM dye in a ratio of 5:1, and then 5 μL of the working solution was added to 200 μg of sample and thoroughly mixed by pipetting. The samples were incubated at room temperature for 30 min while protected from light. A microscopic analysis was performed using Zetaview (Particle Matrix, Germany), equipped with a 520 nm laser, a 550 nm long pass cutoff filter, and an sCOMS camera.
- Transmission electron microscopy: Exosome samples were fixed with 2% paraformaldehyde for a minimum of 2 h at 4 °C, followed by adsorption onto glow-charged copper grids coated with formvar–carbon (#FCF-Cu-50, Electron Microscopy Sciences, Hadfield, PA, USA) for 20 min. Subsequently, after washing with 0.1 M phosphate buffer, the bound exosomes were fixed with 1% glutaraldehyde for 5 min. After washing with distilled water, the samples were negatively stained with 1% uranyl acetate for 1 min. The grids were air-dried and imaged using a FEI Technai G2 Spirit transmission electron microscope (Thermo Fisher Scientific, Waltham, MA, USA) operating at 80 kV, employing a Macrofire digital camera (Optronics, Inc, Chelmsford, MA, USA) and AMT image capture software version 5.42 (Advanced Microscopy Techniques, Woburn, MA, USA).
- Protein extraction and western blot: Protein extraction and western blot were performed as described previously [29]. Briefly, protein extraction was performed using a 1X RIPA buffer (#R-0278, Sigma Aldrich, St. Louis, MO, USA) containing 1X HaltTM protease and a phosphatase inhibitor cocktail (#78442, Thermo Fisher Scientific, Waltham, MA, USA). The protein concentration was quantified using the Bradford assay (#B6916, Sigma Aldrich, St. Louis, MO, USA) and 30 μg of protein was loaded onto 4–16% gradient SDS-PAGE denaturing gels. Further, the proteins were transferred to the polyvinylidene fluoride membranes, blocked with 5% BSA solution in 1X TBST-T and probed using target-specific antibodies. The exosomal markers in the protein extracts from the Malme-3M exosomes were determined using antibodies specific for CD63, CD9, and CD81 (#EXOAB-CD63A-1, #EXOAB-CD9A-1, #EXOAB-CD81A-1 SBI, Palo Alto, CA, USA). To determine the ABC transporters, the EMT markers, and the MMPs, protein extracts from Malme-3M exosomes were determined using antibodies specific for ABCC1, ABCC2, ABCB1, ABCG2, N-cadherin, E-cadherin, MMP2, and MMP9 (#72202, #125595, #13342, #42078, #13116, #3195, #87809, #13667). β-actin (#4970, CST, Denver, MA, USA) was used as a loading control. For detection, anti-rabbit IgG, an HRP-linked secondary antibody (#7074, CST, Denver, MA, USA), and a SuperSignal West Femto Maximum Sensitivity Substrate (#34095, Thermo Fisher Scientific, Waltham, MA, USA) were used.
- RNA extraction and RT-qPCR: The RNA was extracted, and RT-qPCR was performed as previously described [44]. Briefly, the total RNA was extracted using an IBI Scientific total RNA extraction kit (Dubuque, IA, USA), following the manufacturer’s protocol. Up to 2000 ng of complementary DNA (cDNA) was synthesized from isolated exosomal RNA. Further, quantitative real-time polymerase chain reaction (qRT-PCR) was performed using Applied Biosystems reagents (Thermo Fisher Scientific, Waltham, MA, USA) following the manufacturer’s protocol. The primers used were GH (Forward: AGGAAACACAACAGAAATCC, Reverse: TTAGGAGGTCATAGACGTTG). The expression levels of differentially expressed RNAs were compared using the 2-ΔΔCT method. β-actin (Forward: GACGACATGGAGAAAATCTG, Reverse: ATGATCTGGGTCATCTTCTC) was used as an internal control for the RNA analysis.
- Cell migration assay: The cells were seeded at 30,000 cells per well in 12-well plates. After 24 h, a scratch wound was made using a 200 µL pipette tip along the midline of each well. The cultures were gently washed with PBS to remove the loose cells. The cells were maintained in the respective media with Exocontrol (from PBS-treated cells), ExoGH (from GH-treated cells), Exodoxo (from doxorubicin-treated cells), ExoGH+doxo (from cells treated with GH and doxorubicin), and ExoGH+doxo+Peg (from cells treated with GH, doxorubicin, and pegvisomant) for 24 h. For each treatment, 20 μg/mL of exosomes were added [45,46,47]. The scratch area was imaged at the start and end of the assay using a BioTek citation-3 microplate imager (Gen5v2.09.2 software) and quantified using ImageJ software (version 1.8.0_345). Three individual experiments were performed.
- Drug retention assay: Melanoma cells were treated for 12 h with Exocontrol, ExoGH, Exodoxo, ExoGH+doxo, and ExoGH+doxo+Peg. On the day of the assay, the cells were trypsinized, counted, and suspended in cold DiOC2(3) dye on ice for 30 min (EMD Millipore, ECM 910). The cells were then centrifuged, the supernatant was removed, and the cell pellets were resuspended in a cold efflux buffer. The resuspended cells were distributed in equal parts with one set serving as the control and the other two parts kept in a 37 °C water bath for 20 min and 60 min, respectively. The cells were then washed, resuspended, and the cells’ suspension was dispended into the wells of a black-walled 96-well plate. Fluorescence was measured using the fluorescent BioTek citation-3 microplate imager (Gen5v2.09.2 software) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Two individual experiments were performed for each cell line.
- Chemosensitivity assay: MALME-3M, SK-MEL-28, and SK-MEL-30 cells were seeded at 500 cells per 50 µL per well in a 96-well plate. After incubating for 24 h, the cells were treated with 20 µg/mL of Exocontrol, ExoGH, Exodoxo, ExoGH+doxo, and ExoGH+doxo+Peg. Twelve hours later, the cells were exposed to a dose titration of doxorubicin at the specified concentrations in 25 µL. The cell viability was assessed 72 h after doxorubicin treatment as previously described [48].
- Statistical Analysis: For all the experiments, the analysis was performed by one-way or two-way ANOVA with Tukey’s multiple comparison test using GraphPad Prism 8.0 (GraphPad Software). p < 0.05 (*), p < 0.01 (**), and p < 0.001 (***) were considered statistically significant.
3. Results
3.1. GHR Antagonism Suppresses Melanoma Exosome-Mediated Increase in Drug Efflux
3.2. GH Elevates the Expression of ABC Transporters in Melanoma-Derived Exosomes and in Corresponding Recipient Cells
3.2.1. Effects of GH on ABC Transporters in Melanoma-Derived Exosomes
3.2.2. Effects of GH-Induced Melanoma-Derived Exosomes on Recipient Cells
3.3. Blocking Autocrine/Paracrine GH Action Attenuates Exosomal ABC Transporter Levels
3.4. Pegvisomant Treatment of Donor Melanoma Cells Attenuates Exosomal EMT-Inducing Effects
3.5. GH Elevates the Expression of N-cadherin and MMP2 in Melamona-Derived Exosomes and Only Transfers N-cadherin to Recipient Cells
3.5.1. Effects of GH on Cadherins and MMPs in Melanoma-Derived Exosomes
3.5.2. Effects of GH-Induced Melanoma-Derived Exosomes on Cadherins and MMPs in Recipient Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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ABC Transporter | Cell Lines | Exosomes | ||||
---|---|---|---|---|---|---|
Control | GH | Doxo | Doxo + GH | Doxo + GH + Peg | ||
ABCC1 | Malme-3M | 1.0 | 5.0 | 5.4 | 4.9 | 1.4 |
SK-MEL-28 | 1.0 | 2.4 | 3.3 | 3.3 | 1.7 | |
SK-MEL-30 | 1.0 | 7.2 | 6.0 | 6.1 | 1.4 | |
ABCC2 | Malme-3M | 1.0 | 2.8 | 2.4 | 2.5 | 0.8 |
SK-MEL-28 | 1.0 | 2.2 | 2.5 | 3.4 | 2.3 | |
ABCB1 | SK-MEL-30 | 1.0 | 3.3 | 3.9 | 5.6 | 1.9 |
Malme-3M | 1.0 | 3.2 | 3.9 | 3.5 | 1.2 | |
ABCG2 | SK-MEL-28 | 1.0 | 1.4 | 1.5 | 1.6 | 1.0 |
SK-MEL-30 | 1.0 | 2.7 | 3.2 | 2.9 | 1.9 | |
Recipient cells | ||||||
ExoControl | ExoGH | ExoDoxo | ExoDoxo+GH | ExoDoxo+GH+Peg | ||
ABCC1 | Malme-3M | 1.0 | 2.0 | 2.0 | 1.6 | 0.5 |
SK-MEL-28 | 1.0 | 1.0 | 1.6 | 1.4 | 0.8 | |
ABCB1 | Malme-3M | 1.0 | 1.5 | 1.8 | 1.5 | 0.7 |
SK-MEL-28 | 1.0 | 1.0 | 1.3 | 1.1 | 0.5 | |
SK-MEL-30 | 1.0 | 1.5 | 2.1 | 1.5 | 0.9 | |
ABCG2 | Malme-3M | 1.0 | 3.1 | 3.7 | 5.0 | 2.7 |
SK-MEL-28 | 1.0 | 1.6 | 2.9 | 3.2 | 0.9 | |
SK-MEL-30 | 1.0 | 1.7 | 1.3 | 1.5 | 1.8 |
ABC Transporter | Cell Lines | Exosomes | ||||
---|---|---|---|---|---|---|
Control | GH | Doxo | Doxo + GH | Doxo + GH + Peg | ||
MMP2 | Malme-3M | 1.0 | 1.6 | 1.6 | 2.0 | 1.0 |
SK-MEL-28 | 1.0 | 2.0 | 2.1 | 2.3 | 1.4 | |
SK-MEL-30 | 1.0 | 1.9 | 1.4 | 2.0 | 0.7 | |
N-cadherin | Malme-3M | 1.0 | 1.0 | 2.0 | 3.5 | 1.6 |
SK-MEL-28 | 1.0 | 0.8 | 0.8 | 0.8 | 1.9 | |
SK-MEL-30 | 1.0 | 4.5 | 1.7 | 4.0 | 2.9 | |
Recipient Cells | ||||||
ExoControl | ExoGH | ExoDoxo | ExoDoxo+GH | ExoDoxo+GH+Peg | ||
MMP2 | Malme-3M | 1.0 | 1.2 | 1.1 | 1.0 | 0.8 |
SK-MEL-28 | 1.0 | 0.8 | 1.9 | 0.8 | 0.8 | |
SK-MEL-30 | 1.0 | 1.6 | 1.8 | 2.0 | 1.4 | |
N-cadherin | Malme-3M | 1.0 | 2.5 | 1.9 | 3.1 | 1.5 |
SK-MEL-28 | 1.0 | 2.0 | 1.4 | 1.9 | 1.2 | |
SK-MEL-30 | 1.0 | 1.0 | 1.2 | 1.0 | 0.7 |
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Kulkarni, P.; Basu, R.; Bonn, T.; Low, B.; Mazurek, N.; Kopchick, J.J. Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes. Cancers 2024, 16, 2636. https://doi.org/10.3390/cancers16152636
Kulkarni P, Basu R, Bonn T, Low B, Mazurek N, Kopchick JJ. Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes. Cancers. 2024; 16(15):2636. https://doi.org/10.3390/cancers16152636
Chicago/Turabian StyleKulkarni, Prateek, Reetobrata Basu, Taylor Bonn, Beckham Low, Nathaniel Mazurek, and John J. Kopchick. 2024. "Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes" Cancers 16, no. 15: 2636. https://doi.org/10.3390/cancers16152636
APA StyleKulkarni, P., Basu, R., Bonn, T., Low, B., Mazurek, N., & Kopchick, J. J. (2024). Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes. Cancers, 16(15), 2636. https://doi.org/10.3390/cancers16152636