Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

Abstract

Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

“…This occurs either through DNA damage or the targeting of structures critically involved in cell cycle regulation and results in the activation of cell cycle checkpoint arrest programs and induces apoptosis when repair fails. The vast majority of anticancer drugs and ionizing irradiation induce apoptotic cell death through the mitochondrial pathway of apoptosis in a death receptor-independent manner Mrozek et al, 2003). Here, we show that As 2 O 3 , a reagent successfully employed in the treatment of APL and recently also in solid tumors, induces a regulated form of necrotic death.…”

Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

“…Apart from overcoming resistance, our present data and results from other groups show that the combination of anticancer drugs with TRAIL allows to employ significantly lower, subtoxic doses of these compounds to achieve tumor cell killing. In view of our previous findings on clinical resistance to anticancer therapy in consequence of disrupted p53/ Bax signaling (Sturm et al, 1999Prokop et al, 2000;Bosanquet et al, 2002;Gu¨ner et al, 2002;Mrozek et al, 2002), we aimed to clarify the role of Bax in TRAIL-induced sensitization for drug-induced cell death in human carcinoma. Here, we show that TRAIL critically depends on Bax to exert its sensitizing effect.…”

“…Disruption of mitochondrial apoptosis signaling and concomittant development of resistance to anticancer therapy occurs, for example, in consequence of overexpression of antiapoptotic members of the Bcl-2 family such as Bcl-2 or Bcl-x L , or through the loss of proapoptotic Bcl-2 homologs such as Bax or Bak . Given the frequent inactivation of the proapoptotic Bcl-2 homolog Bax in human malignancies (Sturm et al, 1999Gu¨ner et al, 2002;Mrozek et al, 2002;Schelwies et al, 2002), we therefore aimed to investigate the impact of Bax loss on TRAIL sensitivity and sensitization for drug-induced apoptosis by TRAIL. Here, we show that TRAIL depends on Bax to mediate induction of apoptosis.…”

Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

“…S2 shows sensitization of Bax-proficient DU145 cells to TRAIL-induced apoptosis upon sorafenib and roscovitine treatment. with tumor progression and a bad prognosis in colon, esophageal, and gastric carcinoma (Sturm et al, 1999Ionov et al, 2000;Mrózek et al, 2003). Other studies suggest that mismatch repair defects in hematopoietic tumors are linked to Bax tumor suppressor frameshift mutations and that the resulting resistance to apoptosis may be a key feature of some lymphomas and leukemias (Brimmell et al, 1998;Meijerink et al, 1998).…”