Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma

Abstract

PLK1 is essential for the maintenance of genomic stability during mitosis. In our study, we found that overexpression of PLK1 was an independent prognostic factor (RR 5 4.253, p 5 0.020) and significantly correlated with survivin, an antiapoptotic protein, in esophageal squamous cell carcinoma (ESCC). Reverse transcription-polymerase chain reaction and fluorescence in situ hybridization (FISH) revealed upregulation of PLK1 mRNA and amplification of PLK1 gene, respectively. Depletion of PLK1 activated the intrinsic apoptotic pathway, which was substantiated by loss of mitochondrial membrane potential, reduction of Mcl-1 and Bcl-2 as well as activation of caspase-9. Coimmunoprecipitation and confocal microscopy displayed that PLK1 was associated with survivin and PLK1 depletion led to downregulation of survivin. Cotransfection of survivin constructs could partially reverse PLK1-depletion-induced apoptosis. These data suggest that PLK1 might be a useful prognostic marker and a potential therapeutic target for ESCC. Survivin is probably involved in antiapoptotic function of PLK1. ' 2008 Wiley-Liss, Inc.Key words: PLK1; esophageal squamous cell carcinoma; prognosis; apoptosis; survivin Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies worldwide. Although the use of earlier detection and improved therapeutic strategies results in a moderate reduction in mortality rates, the risk to sustain a recurrence of disease remains high. Furthermore, it remains unclear which treatment strategies should be used to best improve an individual patients' survival time, as there are not good therapeutic and prognostic markers. With accumulated information about molecular changes in the carcinogenesis and tumor progression, molecular targeted modulation of signal transduction pathways that are functionally abnormal in carcinogenesis and malignant development is becoming a novel therapeutic strategy. Among them, cell cycle kinases have attracted special attention, given the relevance of cell proliferation to oncogenic processes. Increasing data indicate that the aberrance of cell cycle kinases might lead to 2 cancer-related errors: unlimiting cell proliferation and abnormal cell division leading to chromosomal instability.Polo-like kinase 1 (PLK1) is a key regulator of DNA damage checkpoint, centrosome maturation, chromosome condensation, chromosome segregation and cytokinesis. 1 PLK1 is able to physically associate with multiple important cellular proteins such as p53, Chk2 and cyclin B1. 2-4 Ectopic expression of PLK1 in NIH 3T3 cells leads to transformation in vitro and in vivo. 5 PLK1 was overexpressed in several solid tumors such as breast, bladder, gastric, ovarian and colorectal cancers. [6][7][8][9][10] In our work, we found amplification and overexpression of PLK1 in ESCC when compared with normal esophageal tissues. Our results showed that alterations of PLK1 may be an independent prognostic factor in ESCC and found that PLK1 depletion induced apoptosis via mitochondria signaling pathways by po...

Overexpression of polo-like kinase1 predicts a poor prognosis in hepatocellular carcinoma patients

“…[5] . As a cell cycle control kinase, polo-like kinase1 (PLK1) and its overexpression are highly associated with many human cancers, including bladder [6] , breast [7][8][9][10] , colorectal [11,12] , endometrial [13,14] , esophageal [15][16][17] , gastric [18][19][20][21] , glioma [22] , hepatoblastoma [23] , hepatocellular carcinoma [24] , head and neck [25] , leukemia and lymphoma [26,27] , melanoma [28,29] , nonsmall-cell lung [30] , ovarian [31] , papillary [32] , pancreatic [33,34] , prostate [35] and thyroid cancer [36] . However, up to now, as far as we know, there are few studies available on the overexpression of PLK in HCC.…”

PLK1 Is Transcriptionally Activated by NF-κB during Cell Detachment and Enhances Anoikis Resistance through Inhibiting β-Catenin Degradation in Esophageal Squamous Cell Carcinoma

“…Tissue microarrays (TMA) containing 125 primary esophageal tumors and the corresponding normal epithelia were created, and immunohistochemical analysis was done as described previously (9). TMAs were incubated with an anti-RelA antibody (sc-8008; Santa Cruz Biotechnology) or an anti-PLK1 antibody (Upstate).…”

“…PLK1 has been reported to be upregulated in several solid tumors, such as esophageal, breast, ovarian, prostate, and colon cancer (6)(7)(8)(9). Inhibition of PLK1 with antisense oligonucleotides, siRNA, or dominant-negative mutations leads to mitotic catastrophe, apoptosis, and tumor inhibition (10)(11)(12).…”

From molecules and cells to diseases: West meets East for medical research in Tianjin

“…Professor Wang presented evidence that PLK1 inhibits the mitochondrial apoptosis pathway through a mechanism involving survivin, whereas conformal radiotherapy regulates the transcription of CTTN through STAT3, providing molecular targets in oesophageal cancer [11].…”