NF-κB and Poly (ADP-ribose) Polymerase 1 Form a Positive Feedback Loop that Regulates DNA Repair in Acute Myeloid Leukemia Cells

Abstract

NF-kB mediates acquired resistance in acute myeloid leukemia (AML) cells treated with DNA-damaging agents. Because DNA repair is the major molecular shift that alters sensitivity to DNA-damaging agents, we explored whether activation of the NF-kB pathway promotes AML cell survival by regulating DNA repair after chemotherapy. Our results showed that RELA, an important subunit of NF-kB, regulated DNA repair by binding to the promoter region of the PARP1 gene and affecting PARP1 gene transcription. Conversely, PARP1 knockdown reduced NF-kB activity, indicating that NF-kB and PARP1 create a positive feedback loop in DNA repair. Simultaneous treatment with the NF-kB inhibitor BMS-345541 and the PARP1 inhibitor olaparib resulted in robust killing of AML cells. This dual inhibition significantly suppressed tumor growth and extended survival times in xenograft tumor models. Implications: RELA and PARP1 form a positive feedback loop to regulate DNA damage repair, simultaneous inhibition of NF-kB and PARP1 increases the antileukemic efficacy of daunorubicin in vitro and in vivo, broadening the use of PARP1 inhibitors.

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

“…Flow cytometry analysis was performed as previously described (Li et al, 2019). After 7 days of differentiation in culture conditions, BMDMs were collected, washed with PBS, resuspended in 100 μl of binding buffer (BD Pharmingen, San Diego, CA, United States), labeled with 5 μl of CD11b-APC (561690, BD Biosciences, San Jose, CA, United States) and 5 μl of F4/80-PE (565410, BD Biosciences, San Jose, CA, United States) and incubated for 15 min in the dark.…”

The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors

“…Moreover, p65-deficient AML cells were characterized by decreased mRNA and protein levels of PARP1. Interestingly, knockdown of both PARP1 and RELA resulted in more robust damage accumulation in comparison to knockdown of either of these separately [151]. RELA may indirectly influence PARP1 activity through regulating uc002jit.1, long noncoding RNA (lncRNA) that is thought to stabilize the mRNA of PARP1, as well as prevent it from degradation in the cytoplasm.…”

PARP1 and PRC2 double deficiency promotes BRCA‐proficient breast cancer growth by modification of the tumor microenvironment

“…We found that PARP1-PRC2 double depletion induces activation of the NF-jB pathway, which has known roles in promoting breast cancer [31]. Confusingly, there is evidence that PARP1 and PRC2 both positively and negatively regulate the NF-jB pathway [40][41][42][43][44][45][46]. For example, PARP1 activates the NF-jB pathway in smooth muscle cells, skin cancer, and AML [40][41][42], but inhibits it in osteoclasts [43].…”

“…Confusingly, there is evidence that PARP1 and PRC2 both positively and negatively regulate the NF-jB pathway [40][41][42][43][44][45][46]. For example, PARP1 activates the NF-jB pathway in smooth muscle cells, skin cancer, and AML [40][41][42], but inhibits it in osteoclasts [43]. Likewise, PRC2 activates the NF-jB pathway in adult T-cell leukemia [44], but suppresses it in non-small cell lung cancer and skin cancer [45,46].…”