Per2 Inhibits K562 Leukemia Cell Growth In Vitro and In Vivo Through Cell Cycle Arrest and Apoptosis Induction

Abstract

Per2 regulates other molecular and biochemical processes beyond their established role in the regulation of the mammalian circadian clock, herein we investigated the growth inhibiting potential of Per2 in human K562 leukemia cells and the underlying mechanisms. The results showed that over-expression of Per2 induced not only cell cycle arrest at G2/M phase but also an increase in apoptosis, which was confirmed by characteristic morphological changes, FCM and evident DNA fragmentation. Further experiments confirmed both up-regulation of P53 and down-regulation of CylinB1and C-myc. On the other hand, while P53 was found to be down-regulated. CylinB1 and C-myc were up-regulated. after Per2 knockdown. In leukemia mice, Per2 transfection was shown to suppress cellular proliferation and accelerate apoptosis of K562 cells. Moreover, fewer leukemia cells were found to have infiltrated into the livers and spleens of the mice from the Per2 transfected group as compared with those from the control group. In summary, Per2 displayed a significant anti-tumor effect through cell cycle arrest and apoptosis induction in K562 cells. These data further support the emerging role of the circadian clock in critical aspects of cancer development and thorough research is underway on the mechanism of Per2 in the leukemia.

Down-Regulation of PER2 Increases Apoptosis of Gliomas after X-Ray Irradiation

“…We have investigated the role of PER2 in glioma. Evidence from initial research implicated PER2 as a regulator of the circadian clock [14,[23][24][25]; more recently evidence has expanded on the function of PER2 function to include the promotion of apoptosis in cancer [9,11]. We hypothesized that PER2 is also a tumor suppressor gene.…”

“…After comprehensively surveying the links between PER2 and TP53 in previous reports [2,4,[9][10][11][12][13][14][15], we selected wild-type TP53 human U343 glioma cells, then RNA interference technology and shRNA-lentivirus were used to downregulate PER2. However, we found that following treatment with 6 mV, 100cGy of X-ray irradiation, DNA damage was observed in both two groups after 24 h, and shRNA-PER2-transfected cells showed more serious DNA tailing phenomena and significantly increased death rate compared with control cells.…”

“…In addition, clear differences in PER2 expression are evident in tumor tissue and non-involved peripheral tissues [3][4][5][6][7]. Elsewhere, overexpression and/or or mutations in the PER2 gene have been reported to correlate with enhanced tumor growth in breast cancer, colon cancer and lymphoma, corresponding with altered expression of TP53 and the oncogenes BCLxl, BCL-2, cyclinB1, cyclin D, cyclin E and C-MYC [8][9][10][11][12][13][14][15]. PER2 has also been linked with DNA damage response pathways [16].…”

“…PER2 has also been linked with DNA damage response pathways [16]. X-ray-induced DNA damage in tumor cell lines with mutated PER2 exhibited increased sensitivity to damage affecting cell proliferation, apoptosis, and the TP53 pathway [17][18][19].…”

Circadian Rhythms in Stem Cell Biology and Function

“…C-MYC directly blocks cyclin D1 activity, which is a roadblock for G1/S phase transition in the cell cycle. Overexpression of Per2 concomitantly leads to cell cycle arrest in certain cancer cell lines and pushes these cells into apoptosis (Hua et al 2006 ;Oda et al 2009 ;Sun et al 2010 ). Recently, a relatively new clock player termed NONO has also been implicated in cell cycle regulation.…”