Fumin Lin1, Kathrina L Marcelo1, Kimal Rajapakshe1, Cristian Coarfa1, Adam Dean1, Nathaniel Wilganowski2,3, Holly Robinson2,3, Eva Sevick2,3, Karl-Dimiter Bissig1,4,5, Lauren C Goldie5,6,7, Anthony R Means1,4, Brian York1,4. 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX. 2. The University of Texas Health Science Center, Houston, TX. 3. Center for Molecular Imaging, Institute of Molecular Medicine, Houston, TX. 4. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX. 5. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX. 6. Department of Pediatrics, Baylor College of Medicine, Houston, TX. 7. USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX.
Abstract
UNLABELLED: Hepatic cancer is one of the most lethal cancers worldwide. Here, we report that the expression of Ca(2+) /calmodulin-dependent protein kinase kinase 2 (CaMKK2) is significantly up-regulated in hepatocellular carcinoma (HCC) and negatively correlated with HCC patient survival. The CaMKK2 protein is highly expressed in all eight hepatic cancer cell lines evaluated and is markedly up-regulated relative to normal primary hepatocytes. Loss of CaMKK2 function is sufficient to inhibit liver cancer cell growth, and the growth defect resulting from loss of CaMKK2 can be rescued by ectopic expression of wild-type CaMKK2 but not by kinase-inactive mutants. Cellular ablation of CaMKK2 using RNA interference yields a gene signature that correlates with improvement in HCC patient survival, and ablation or pharmacological inhibition of CaMKK2 with STO-609 impairs tumorigenicity of liver cancer cells in vivo. Moreover, CaMKK2 expression is up-regulated in a time-dependent manner in a carcinogen-induced HCC mouse model, and STO-609 treatment regresses hepatic tumor burden in this model. Mechanistically, CaMKK2 signals through Ca(2+) /calmodulin-dependent protein kinase 4 (CaMKIV) to control liver cancer cell growth. Further analysis revealed that CaMKK2 serves as a scaffold to assemble CaMKIV with key components of the mammalian target of rapamycin/ribosomal protein S6 kinase, 70 kDa, pathway and thereby stimulate protein synthesis through protein phosphorylation. CONCLUSION: The CaMKK2/CaMKIV relay is an upstream regulator of the oncogenic mammalian target of rapamycin/ribosomal protein S6 kinase, 70 kDa, pathway, and the importance of this CaMKK2/CaMKIV axis in HCC growth is confirmed by the potent growth inhibitory effects of genetically or pharmacologically decreasing CaMKK2 activity; collectively, these findings suggest that CaMKK2 and CaMKIV may represent potential targets for hepatic cancer.
UNLABELLED: Hepatic cancer is one of the most lethal cancers worldwide. Here, we report that the expression of Ca(2+) /calmodulin-dependent protein kinase kinase 2 (CaMKK2) is significantly up-regulated in hepatocellular carcinoma (HCC) and negatively correlated with HCCpatient survival. The CaMKK2 protein is highly expressed in all eight hepatic cancer cell lines evaluated and is markedly up-regulated relative to normal primary hepatocytes. Loss of CaMKK2 function is sufficient to inhibit liver cancer cell growth, and the growth defect resulting from loss of CaMKK2 can be rescued by ectopic expression of wild-type CaMKK2 but not by kinase-inactive mutants. Cellular ablation of CaMKK2 using RNA interference yields a gene signature that correlates with improvement in HCCpatient survival, and ablation or pharmacological inhibition of CaMKK2 with STO-609 impairs tumorigenicity of liver cancer cells in vivo. Moreover, CaMKK2 expression is up-regulated in a time-dependent manner in a carcinogen-induced HCCmouse model, and STO-609 treatment regresses hepatic tumor burden in this model. Mechanistically, CaMKK2 signals through Ca(2+) /calmodulin-dependent protein kinase 4 (CaMKIV) to control liver cancer cell growth. Further analysis revealed that CaMKK2 serves as a scaffold to assemble CaMKIV with key components of the mammalian target of rapamycin/ribosomal protein S6 kinase, 70 kDa, pathway and thereby stimulate protein synthesis through protein phosphorylation. CONCLUSION: The CaMKK2/CaMKIV relay is an upstream regulator of the oncogenic mammalian target of rapamycin/ribosomal protein S6 kinase, 70 kDa, pathway, and the importance of this CaMKK2/CaMKIV axis in HCC growth is confirmed by the potent growth inhibitory effects of genetically or pharmacologically decreasing CaMKK2 activity; collectively, these findings suggest that CaMKK2 and CaMKIV may represent potential targets for hepatic cancer.
Authors: K A Anderson; R L Means; Q H Huang; B E Kemp; E G Goldstein; M A Selbert; A M Edelman; R T Fremeau; A R Means Journal: J Biol Chem Date: 1998-11-27 Impact factor: 5.157
Authors: Tomohiro Koga; Christian M Hedrich; Masayuki Mizui; Nobuya Yoshida; Kotaro Otomo; Linda A Lieberman; Thomas Rauen; José C Crispín; George C Tsokos Journal: J Clin Invest Date: 2014-03-25 Impact factor: 14.808
Authors: Mohd Altaf Najar; D A B Rex; Prashant Kumar Modi; Nupur Agarwal; Shobha Dagamajalu; Gayathree Karthikkeyan; Manavalan Vijayakumar; Aditi Chatterjee; Uma Sankar; T S Keshava Prasad Journal: J Cell Commun Signal Date: 2020-11-02 Impact factor: 5.782
Authors: Christopher G Langendorf; Matthew T O'Brien; Kevin R W Ngoei; Luke M McAloon; Urmi Dhagat; Ashfaqul Hoque; Naomi X Y Ling; Toby A Dite; Sandra Galic; Kim Loh; Michael W Parker; Jonathan S Oakhill; Bruce E Kemp; John W Scott Journal: J Biol Chem Date: 2020-09-09 Impact factor: 5.157
Authors: Kathrina L Marcelo; Thomas Ribar; Christopher R Means; Anna Tsimelzon; Robert D Stevens; Olga Ilkayeva; James R Bain; Susan G Hilsenbeck; Christopher B Newgard; Anthony R Means; Brian York Journal: Mol Endocrinol Date: 2016-03-22