Schmitt Clemens A, Fridman Jordan S, Yang Meng, Lee Soyoung, Baranov Eugene, Hoffman Robert M, Lowe Scott W
Cold Spring Harbor Laboratory, 1 Bungtown Road, New York 11724, USA.
Cell. 2002 May 3;109(3):335-46. doi: 10.1016/s0092-8674(02)00734-1.
p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a). Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo. Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.
p53和INK4a/ARF突变部分通过抑制细胞凋亡来促进肿瘤发生和耐药性。我们发现原发性小鼠淋巴瘤也通过启动由p53和p16(INK4a)控制的衰老程序来对化疗产生反应。因此，具有p53或INK4a/ARF突变的肿瘤——但不包括仅缺乏ARF的肿瘤——在体内对环磷酰胺治疗反应不佳。此外，具有Bcl2介导的凋亡阻滞的肿瘤会经历药物诱导的细胞停滞，涉及p53、p16(INK4a)和衰老标志物的积累，并且在进展到终末期时通常会获得p53或INK4a突变。最后，携带能够发生药物诱导衰老的肿瘤的小鼠在化疗后的预后比那些具有衰老缺陷肿瘤的小鼠要好得多。因此，细胞衰老在体内对治疗结果有影响。
