Parp‐1 genetic ablation in Ela–myc mice unveils novel roles for Parp‐1 in pancreatic cancer

Abstract

Pancreatic cancer has a dismal prognosis and is currently the fourth leading cause of cancer-related death in developed countries. The inhibition of poly(ADP-ribose) polymerase-1 (Parp-1), the major protein responsible for poly(ADP-ribosy)lation in response to DNA damage, has emerged as a promising treatment for several tumour types. Here we aimed to elucidate the involvement of Parp-1 in pancreatic tumour progression. We assessed Parp-1 protein expression in normal, preneoplastic and pancreatic tumour samples from humans and from K-Ras- and c-myc-driven mouse models of pancreatic cancer. Parp-1 was highly expressed in acinar cells in normal and cancer tissues. In contrast, ductal cells expressed very low or undetectable levels of this protein, both in a normal and in a tumour context. The Parp-1 expression pattern was similar in human and mouse samples, thereby validating the use of animal models for further studies. To determine the in vivo effects of Parp-1 depletion on pancreatic cancer progression, Ela-myc-driven pancreatic tumour development was analysed in a Parp-1 knock-out background. Loss of Parp-1 resulted in increased tumour necrosis and decreased proliferation, apoptosis and angiogenesis. Interestingly, Ela-myc:Parp-1(-/-) mice displayed fewer ductal tumours than their Ela-myc:Parp-1(+/+) counterparts, suggesting that Parp-1 participates in promoting acinar-to-ductal metaplasia, a key event in pancreatic cancer initiation. Moreover, impaired macrophage recruitment can be responsible for the ADM blockade found in the Ela-myc:Parp-1(-/-) mice. Finally, molecular analysis revealed that Parp-1 modulates ADM downstream of the Stat3-MMP7 axis and is also involved in transcriptional up-regulation of the MDM2, VEGFR1 and MMP28 cancer-related genes. In conclusion, the expression pattern of Parp-1 in normal and cancer tissue and the in vivo functional effects of Parp-1 depletion point to a novel role for this protein in pancreatic carcinogenesis and shed light into the clinical use of Parp-1 inhibitors.

The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer

“…To evaluate sunitinib effects on cancer cell apoptosis, we analyzed cleaved caspase 3 staining of both acinar and ductal tumor areas (Figure 4A). As previously reported [30], acinar tumors showed increased cell apoptosis compared to ductal ones (Figure 4A, compare a with c), although quantification of cleaved caspase 3 positive areas showed no significant differences between control and sunitinib-treated animals (Figure 4A, right panel). Subsequently, we tested whether sunitinib treatment could inhibit tumor cell growth by measuring cell proliferation using P-Histone H3 for acinar tumors (Figure 4B, a and b) and Ki67 immunostaining for ductal tumors (Figure 4B, c and d) (see Material and Methods).…”

Cytoplasmic PARP‐1 promotes pancreatic cancer tumorigenesis and resistance

“…Using human normal and pancreatic cancer tissues, we determined increased cytoplasmic localization of PARP‐1 in pancreatic cancers, while only nuclear PARP‐1 expression was identified in the normal human pancreatic tissues, suggesting a role of the cytoplasmic PARP‐1 in pancreatic tumor pathogenesis and progression. Previous analysis of PARP‐1 protein expression in normal, preneoplastic and pancreatic tumor indicated that PARP‐1 was highly expressed in acinar cells in normal and cancer tissues, but very low or undetectable levels in the ductal cells . Immunohistochemical assessment of PARP expression in a population‐based cohort of 178 adenocarcinomas of the pancreas found that low‐level nuclear expression of PARP was associated with a poor prognosis .…”

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…Mice deficient in PARP showed decreased susceptibility to skin cancer through decreased NF-κB [35]. A novel role for PARP-1 in pancreatic cancer has been proposed based on the observation that PARP-1 depletion in the Ela-myc mice, a pancreatic cancer progression model, decreased the frequency of early stages of the disease and might be therefore be beneficial in preventing its development and progression [89]. In addition, PARP-1KO mice subjected to chemically-induced (AOM/dextran sodium sulfate) colorectal carcinogenesis were protected from tumor development compared to WT mice that carried significantly more tumors with a more aggressive phenotype characterized by upregulation of cyclin D1 and STAT3 [90].…”