cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53

Abstract

Autophagy is important in regulating the balance between cell death and survival, with the tumor suppressor p53 as one of the key components in this interplay. We have previously utilized an in vitro model of the most common form of childhood cancer, B cell precursor acute lymphoblastic leukemia (BCP-ALL), to show that activation of the cAMP signaling pathway inhibits p53-mediated apoptosis in response to DNA damage in both cell lines and primary leukemic cells. The present study reveals that cAMP-mediated survival of BCP-ALL cells exposed to DNA damaging agents, involves a critical and p53-independent enhancement of autophagy. Although autophagy generally is regarded as a survival mechanism, DNA damage-induced apoptosis has been linked both to enhanced and reduced levels of autophagy. Here we show that exposure of BCP-ALL cells to irradiation or cytotoxic drugs triggers autophagy and cell death in a p53-dependent manner. Stimulation of the cAMP signaling pathway further augments autophagy and inhibits the DNA damage-induced cell death concomitant with reduced nuclear levels of p53. Knocking-down the levels of p53 reduced the irradiation-induced autophagy and cell death, but had no effect on the cAMP-mediated autophagy. Moreover, prevention of autophagy by bafilomycin A1 or by the ULK-inhibitor MRT68921, diminished the protecting effect of cAMP signaling on DNA damage-induced cell death. Having previously proposed a role of the cAMP signaling pathway in development and treatment of BCP-ALLs, we here suggest that inhibitors of autophagy may improve current DNA damage-based therapy of BCP-ALL - independent of p53.

RETRACTED: Correlation between ER, PR, P53, Ki67 expression, and high-risk HPV infection in patients with different levels of cervical intraepithelial neoplasia

“…Overexpression of P53 has been proved to be significantly related to the initiation of HP-HPV transformation infection. 25,26 Ki-67 is a definite marker of nuclear proliferation at present. Its half-life is short.…”

Correlation between ER, PR, P53, Ki67 Expression and High-Risk HPV Infection in Patients with Different Levels of Cervical Intraepithelial Neoplasia

“…It is also a disorder of the entering S phase from G1 phase, thereby inhibiting cell proliferation. Overexpression of p53 has been proved to be significantly related to the initiation of HP-HPV transformation infection [25,26] . Ki67 is a definite marker of nuclear proliferation at present.…”

Resveratrol protects intestinal epithelial cells against radiation-induced damage by promoting autophagy and inhibiting apoptosis through SIRT1 activation

“…However, the mechanisms underlying the reciprocal functional interaction of autophagy-p53 are not yet fully understood. Although p53 induces the transcription of autophagy-related genes, such as AMPK β1/β2 , DRAM and DAPK-1 [ 28 , 29 ], a previous study suggested that lowering the levels of p53 may facilitate autophagy [ 30 ]. In addition, it has been reported that autophagy suppresses p53 expression [ 31 ].…”