PUMA Suppresses Intestinal Tumorigenesis in Mice

Abstract

Defective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. PUMA, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of PUMA in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, PUMA deficiency increased the multiplicity and size of colon tumors but reduced the frequency of β-catenin hotspot mutations. The absence of PUMA led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent PUMA expression and PUMA-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, PUMA deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APC Min/+ mice. These results show an essential role of PUMA-mediated apoptosis in suppressing intestinal tumorigenesis in mice. [Cancer Res 2009;69(12):4999-5006]

Apoptosis promotes early tumorigenesis

“…These findings suggest that both a reduction/expansion of hematopoietic stem/progenitor cell numbers and death of leukocytes are required for PUMA-mediated DNA damage associated lymphoma development (Figure 1d). Somewhat paradoxically, loss of PUMA conversely accelerates c-Myc-induced lymphomagenesis, as well as chemical-mediated intestinal tumorigenesis in mice (Hemann et al, 2004;Michalak et al, 2009;Qiu et al, 2009). c-Myc controls the balance between hematopoietic stem/progenitor cell self-renewal and differentiation The prototypical DAMP, high-mobility group box 1 protein (HMGB1) binds to several receptors including the receptor for advanced glycation end products (RAGE) and sustains inflammation, cell proliferation and autophagy, which in turn promote tumor growth.…”

Context Dependent Role of P53 Up-Regulated Modulator of Apoptosis (Puma) During Liver Degeneration and Regeneration

“…Our group and Qiu W, et al [41] uncovered the long term controversy on the ambivalent role of the proapoptotic BH3 only protein Bid in tumorigenesis [16,[40][41][42] and Puma in carcinogen (i.e. DEN) driven liver cancer model of mice [16]. Loss of BH3 only protein Bid [43] or overexpression of Bcl-2 [44] suppressed DEN-induced liver cancer and hepatocyte proliferation.…”

“…The patho physiologic role of apoptosis is complicated by contradictory evidences where lack of apoptosis or increased apoptosis may both result in carcinogenesis depending on the microenvironment and external influences. Our group and Qiu W, et al [41] uncovered the long term controversy on the ambivalent role of the proapoptotic BH3 only protein Bid in tumorigenesis [16,[40][41][42] and Puma in carcinogen (i.e. DEN) driven liver cancer model of mice [16].…”

“…Inhibition of Puma with short hairpin RNAs suppressed p53-dependent apoptosis, endorsed the oncogenic transformation of primary murine fibroblasts by E1A/Ras and dramatically steps up El-myc-induced lymphomagenesis [15]. Loss of Puma enhanced intestinal tumorigenesis induced by carcinogens [16]. In contrary, two independent studies also demonstrated that Puma dependent apoptosis is required for radiation-induced lymphoma in mice [17,18].…”

“…The loss of Puma activity can also limit the replicative stress by protecting bone marrow hematopoietic cells from death [18]. In contrast the Puma mediated apoptosis drives DEN induced mice model of HCC [16].…”