Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells
Abstract Background Clear cell renal cell carcinoma (ccRCC) is a type of cancer characterized by a vast intracellular accumulation of lipids that are critical to sustain growth and viability of the cells in the tumour microenvironment. Stearoyl-CoA 9-desaturase 1 (SCD-1) is an essential enzyme for t...
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BMC
2024-12-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-024-03611-y |
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| author | Barbara Guerra Kristina Jurcic Rachelle van der Poel Samantha Lynn Cousineau Thomas K. Doktor Laura M. Buchwald Scott E. Roffey Caroline A. Lindegaard Anna Z. Ferrer Mohammad A. Siddiqui Laszlo Gyenis Brage S. Andresen David W. Litchfield |
| author_facet | Barbara Guerra Kristina Jurcic Rachelle van der Poel Samantha Lynn Cousineau Thomas K. Doktor Laura M. Buchwald Scott E. Roffey Caroline A. Lindegaard Anna Z. Ferrer Mohammad A. Siddiqui Laszlo Gyenis Brage S. Andresen David W. Litchfield |
| author_sort | Barbara Guerra |
| collection | DOAJ |
| description | Abstract Background Clear cell renal cell carcinoma (ccRCC) is a type of cancer characterized by a vast intracellular accumulation of lipids that are critical to sustain growth and viability of the cells in the tumour microenvironment. Stearoyl-CoA 9-desaturase 1 (SCD-1) is an essential enzyme for the synthesis of monounsaturated fatty acids and consistently overexpressed in all stages of ccRCC growth. Methods Human clear cell renal cell carcinoma lines were treated with small-molecule inhibitors of protein kinase CK2. Effects on the expression levels of SCD-1 were investigated by RNA-sequencing, RT-qPCR, Western blot, and in vivo studies in mice. Phase-contrast microscopy, fluorescence microscopy, flow cytometry, and MALDI-mass spectrometry analysis were carried out to study the effects on endogenous lipid accumulation, induction of endoplasmic reticulum stress, rescue effects induced by exogenous MUFAs, and the identity of lipid populations. Cell proliferation and survival were investigated in real time employing the Incucyte® live-cell analysis system. Statistical significance was determined by applying the two-tailed Student’s t test when comparing two groups of data whereas the two-way ANOVA, multiple Tukey’s test was employed for multiple comparisons. Results Here, we show that protein kinase CK2 is critical for preserving the expression of SCD-1 in ccRCC lines maintained in culture and heterotransplanted into nude mice. Consistent with this, pharmacological inhibition of CK2 leads to induction of endoplasmic reticulum stress linked to unfolded protein response activation and decreased proliferation of the cells. Both effects could be reversed by supplementing the growth medium with oleic acid indicating that these effects are specifically caused by reduced expression of SCD-1. Analysis of lipid composition by MALDI-mass spectrometry revealed that inhibition of CK2 results in a significant accumulation of the saturated palmitic- and stearic acids. Conclusions Collectively, our results revealed a previously unidentified molecular mechanism regulating the synthesis of monounsaturated fatty acids corroborating the notion that novel therapeutic approaches that include CK2 targeting, may offer a greater synergistic anti-tumour effect for cancers that are highly dependent on fatty acid metabolism. |
| format | Article |
| id | doaj-art-fe3a566d084845079594bc101f6a6d18 |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Cancer Cell International |
| spelling | doaj-art-fe3a566d084845079594bc101f6a6d182024-12-29T12:48:13ZengBMCCancer Cell International1475-28672024-12-0124112210.1186/s12935-024-03611-yProtein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cellsBarbara Guerra0Kristina Jurcic1Rachelle van der Poel2Samantha Lynn Cousineau3Thomas K. Doktor4Laura M. Buchwald5Scott E. Roffey6Caroline A. Lindegaard7Anna Z. Ferrer8Mohammad A. Siddiqui9Laszlo Gyenis10Brage S. Andresen11David W. Litchfield12Department of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry, Western UniversityDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry, Western UniversityDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry, Western UniversityDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry, Western UniversityDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry, Western UniversityAbstract Background Clear cell renal cell carcinoma (ccRCC) is a type of cancer characterized by a vast intracellular accumulation of lipids that are critical to sustain growth and viability of the cells in the tumour microenvironment. Stearoyl-CoA 9-desaturase 1 (SCD-1) is an essential enzyme for the synthesis of monounsaturated fatty acids and consistently overexpressed in all stages of ccRCC growth. Methods Human clear cell renal cell carcinoma lines were treated with small-molecule inhibitors of protein kinase CK2. Effects on the expression levels of SCD-1 were investigated by RNA-sequencing, RT-qPCR, Western blot, and in vivo studies in mice. Phase-contrast microscopy, fluorescence microscopy, flow cytometry, and MALDI-mass spectrometry analysis were carried out to study the effects on endogenous lipid accumulation, induction of endoplasmic reticulum stress, rescue effects induced by exogenous MUFAs, and the identity of lipid populations. Cell proliferation and survival were investigated in real time employing the Incucyte® live-cell analysis system. Statistical significance was determined by applying the two-tailed Student’s t test when comparing two groups of data whereas the two-way ANOVA, multiple Tukey’s test was employed for multiple comparisons. Results Here, we show that protein kinase CK2 is critical for preserving the expression of SCD-1 in ccRCC lines maintained in culture and heterotransplanted into nude mice. Consistent with this, pharmacological inhibition of CK2 leads to induction of endoplasmic reticulum stress linked to unfolded protein response activation and decreased proliferation of the cells. Both effects could be reversed by supplementing the growth medium with oleic acid indicating that these effects are specifically caused by reduced expression of SCD-1. Analysis of lipid composition by MALDI-mass spectrometry revealed that inhibition of CK2 results in a significant accumulation of the saturated palmitic- and stearic acids. Conclusions Collectively, our results revealed a previously unidentified molecular mechanism regulating the synthesis of monounsaturated fatty acids corroborating the notion that novel therapeutic approaches that include CK2 targeting, may offer a greater synergistic anti-tumour effect for cancers that are highly dependent on fatty acid metabolism.https://doi.org/10.1186/s12935-024-03611-yClear cell renal cell carcinomaCK2SCD-1fatty acidssunitinib |
| spellingShingle | Barbara Guerra Kristina Jurcic Rachelle van der Poel Samantha Lynn Cousineau Thomas K. Doktor Laura M. Buchwald Scott E. Roffey Caroline A. Lindegaard Anna Z. Ferrer Mohammad A. Siddiqui Laszlo Gyenis Brage S. Andresen David W. Litchfield Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells Cancer Cell International Clear cell renal cell carcinoma CK2 SCD-1 fatty acids sunitinib |
| title | Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells |
| title_full | Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells |
| title_fullStr | Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells |
| title_full_unstemmed | Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells |
| title_short | Protein kinase CK2 sustains de novo fatty acid synthesis by regulating the expression of SCD-1 in human renal cancer cells |
| title_sort | protein kinase ck2 sustains de novo fatty acid synthesis by regulating the expression of scd 1 in human renal cancer cells |
| topic | Clear cell renal cell carcinoma CK2 SCD-1 fatty acids sunitinib |
| url | https://doi.org/10.1186/s12935-024-03611-y |
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