Inactivation of p53 and of pRb protects human colorectal carcinoma cells against hyperthermia-induced cytotoxicity and apoptosis.
Cell-cycle checkpoints are thought to govern the cellular response to external stimuli. The involvement of the p53 tumour-suppressor protein and the retinoblastoma protein (pRb) in the cell-cycle checkpoint in G1 phase is well established. However, little is known about the importance of these G1 checkpoint regulators in hyperthermia-induced cytotoxicity. Such information is relevant because of the clinical application of hyperthermia in combination with chemotherapy or with radiotherapy. The effects of p53 or pRb inactivation were studied in a well-established isogenic system using the human colorectal carcinoma cell line (RKO). The cells were treated with clinically relevant heat doses (60 min at 40-43 degrees C). Cell survival, cell-cycle redistribution and induction of apoptosis were investigated. Survival of the p53-inactivated transfectants was higher than that of the wild-type p53 cells. The pRb-inactivated transfectants showed an intermediate sensitivity to hyperthermia. All transfectants showed G2 arrest after hyperthermia and the appearance of a sub-G1 population. The induction of apoptosis was inhibited in p53-inactivated and pRb-inactivated transfectants. These results suggest that p53 and/or pRb status may be an important determinant of the clinical response to hyperthermia.
van Bree
C
C
Academic Medical Centre, University of Amsterdam, Department of Medical Oncology, Division of Internal Medicine, Room F0-205, PO Box 22700, 1100 DE Amsterdam, The Netherlands. cvanbree@amc.uva.nl
van der Maat
B
B
Ceha
H M
HM
Franken
N A
NA
Haveman
J
J
Bakker
P J
PJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000628:therapy*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006979:Hyperthermia, Induced; D011878:Radiotherapy / Q000379:methods; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53