Inhibition of acyl-CoA binding protein (ACBP) by means of a GABARγ2-derived peptide.

Acyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABAR) γ2 subunit (GABARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABARγ2 protein in liver hepatocytes but not in other major organs. ACBP/DBI inhibition by systemically injected antibodies has been demonstrated to mediate anorexigenic and organ-protective, autophagy-dependent effects.

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death.

The deletion of the gene coding for poly(ADP-ribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson's disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level.

PARP1 inhibition elicits immune responses against non-small cell lung cancer.

High levels of intracellular poly(ADP-ribose) (PAR) resulting from an elevated activity of PAR polymerase-1 (PARP1) correlate with poor infiltration of non-small cell lung cancers by cytotoxic T lymphocytes and dismal patient prognosis. Preclinical experimentation now demonstrates that PARP1 inhibition in cancer cells mediates strong immunostimulatory effects.

Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer.

Background: High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance.

Methods: Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PAR clones.

Pyridoxal kinase and poly(ADP-ribose) affect the immune microenvironment of locally advanced cancers.

Malignant cells adapt to the hostile tumor microenvironment by escaping from, or actively suppressing, anticancer immune responses. In the past, we reported that reduced synthesis of active vitamin B6 (due to downregulation of pyridoxal kinase) or overactivation of poly(ADP-ribose) polymerase confers resistance to chemotherapy with cisplatin. Recently, we found that these prognostically adverse alterations in oncometabolism also correlate with the rarefaction of immune effectors in the tumor bed.