Progressive decrease of phosphocreatine, creatine and creatine kinase in skeletal muscle upon transformation to sarcoma.
In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We experimentally induced sarcoma in mouse leg muscle by injecting either 3-methylcholanthrene or live sarcoma 180 cells into one hind leg. Creatine, phosphocreatine and creatine kinase isoform levels decreased as malignancy progressed and reached very low levels in the final stage of sarcoma development; all these parameters remained unaltered in the unaffected contralateral leg muscle of the same animal. Creatine and creatine kinase levels were also reduced significantly in frank malignant portions of human sarcoma and gastric and colonic adenocarcinoma compared with the distal nonmalignant portions of the same samples. In mice, immunoblotting with antibodies against cytosolic muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase showed that both of these isoforms decreased as malignancy progressed. Expressions of mRNA of muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase were also severely downregulated. In human sarcoma these two isoforms were undetectable also. In human gastric and colonic adenocarcinoma, brain-type creatine kinase was found to be downregulated, whereas ubiquitous mitochondrial creatine kinase was upregulated. These significantly decreased levels of creatine and creatine kinase isoforms in sarcoma suggest that: (a) the genuine muscle phenotype is lost during sarcoma progression, and (b) these parameters may be used as diagnostic marker and prognostic indicator of malignancy in this tissue.
Patra
Subrata
S
Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India.
Bera
Soumen
S
SinhaRoy
Soumya
S
Ghoshal
Sarani
S
Ray
Subhankar
S
Basu
Abhimanyu
A
Schlattner
Uwe
U
Wallimann
Theo
T
Ray
Manju
M
D000230:Adenocarcinoma / Q000201:enzymology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology; D003401:Creatine / Q000378:metabolism*; D003402:Creatine Kinase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D052276:Creatine Kinase, BB Form / Q000032:analysis; D052283:Creatine Kinase, MM Form / Q000032:analysis; D052281:Creatine Kinase, Mitochondrial Form / Q000032:analysis; D018450:Disease Progression; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009379:Neoplasms, Muscle Tissue / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010725:Phosphocreatine / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012509:Sarcoma / Q000201:enzymology / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology
D012333:RNA, Messenger; D010725:Phosphocreatine; D003402:Creatine Kinase; D052276:Creatine Kinase, BB Form; D052283:Creatine Kinase, MM Form; D052281:Creatine Kinase, Mitochondrial Form; D003401:Creatine