Down regulation of Chk1 by p53 plays a role in synergistic induction of apoptosis by chemotherapeutics and inhibitors for Jak2 or BCR/ABL in hematopoietic cells

Abstract

DNA-damaging chemotherapeutic agents activate apoptotic pathways in cancer cells. However, they also activate checkpoint mechanisms mainly involving Chk1 and p53 to arrest cell cycle progression, thus abbreviating their cytotoxic effects. We previously found that aberrant tyrosine kinases involved in leukemogenesis, such as BCR/ABL and Jak2-V617F, as well as Jak2 activated by hematopoietic cytokines enhance Chk1-mediated G2/M arrest through the PI3K/Akt/GSK3 pathway to confer resistance to chemotherapeutic agents, which was prevented by inhibition of these kinases or the downstream PI3K/Akt pathway. However, the possible involvement of p53 in regulation of Chk1-mediated G2/M checkpoint has remained to be elucidated. We demonstrate here that a dominant negative mutant of p53, p53-DD, increases Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics and protects it from down regulation by inhibition of Jak2, BCR/ABL, or the PI3K/Akt pathway in hematopoietic model cell lines 32D and BaF3 or their transformants by BCR/ABL. Consistent with this, the p53 activator nutlin-3 synergistically induced apoptosis with chemotherapeutics by inhibiting Chk1-mediated G2/M arrest in these cells, including cells transformed by the T315I mutant of BCR/ABL resistant to various kinase inhibitors in clinical use. Further studies suggest that p53 may inhibit the Chk1 pathway by its transcription-dependent function and through mechanisms involving the proteasomal system, but not the PI3K/Akt/GSK3 pathway. The present study may shed a new light on molecular mechanisms for the therapy resistance of p53-mutated hematological malignancies and would provide valuable information for the development of novel therapeutic strategies against these diseases with dismal prognosis.

CXCR1/2 pathways in paclitaxel-induced neuropathic pain

“…Since JAK2, STAT3 and PI3K pathways are also involved in several other activities such as apoptosis and senescence, that are two phenomena that could be induced by anticancer drugs, future investigations will be performed in order to evaluate if treatment with reparixin may have any effect on these phenomena as already described by other Authors in different cancer cells [68–70]. …”

“…Overall the results described in this paper for the first time provide evidences that IL-8 and its receptors CXCR1/2 play a key role in the induction and progression of peripheral neuropathy and reinforce the hypothesis that CXCR1/2 inhibitors combined with standard taxane therapy might potentiate the taxane anti-tumor activity and reduce the chemotherapy-induced neurotoxicity. Since JAK2, STAT3 and PI3K pathways are also involved in several other activities such as apoptosis and senescence, that are two phenomena that could be induced by anticancer drugs, future investigations will be performed in order to evaluate if treatment with reparixin may have any effect on these phenomena as already described by other Authors in different cancer cells [ 68 – 70 ].…”

Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway

“…Akt can be activated by the lipid kinase PI3K through generating the second messenger PIP3 (phosphatidylinositol-3,4,5- triphosphate). GSK-3β is an important downstream molecule of Akt, which has close relationship with cellular proliferation, migration, apoptosis, cell cycle and glucose regulation ( Ali et al, 2001 ; Umezawa et al, 2016 ). Activation of the PI3K-Akt-GSK-3β signaling pathway makes the downstream transcription factor Snail more stable to repress the expression of gene CDH 1 encoding E-cadherin, promoting EMT process ( Lamouille et al, 2014 ).…”

Anti-inflammatory effect of Man-Pen-Fang, a Chinese herbal compound, on chronic pelvic inflammation in rats

“…The results of quantitative RT-PCR showed that the expressions of P53 mRNA, Fas/FasL mRNA, and MMP-2 mRNA in uterus were significantly elevated after treatment with MPF and the expression of TGF-β1 mRNA was reduced. The expression of P53 mRNA, Fas/FasL mRNA, and MMP-2 mRNA all have an effect to promote the apoptosis (Kitamura et al, 2001;Dmitrieva et al, 2003;Smane et al, 2013;Zhang et al, 2015;Umezawa et al, 2016). High expression of TGF-β1 mRNA can induce the activation of anti-apoptotic cytokine NF-κb, resulting in blocking of inflammatory cells'…”