p53 as a tumor suppressor protein has been implicated in multiple aspects of biological processes, including apoptosis, cell cycle arrest, senescence, metabolism, differentiation and angiogenesis. Recently, several studies have shown that p53 can induce autophagy in both transcription-dependent and -independent manners. Nonetheless, p53 may also inhibit autophagy. In addition, p53 participates in homeostatic regulation of energy metabolism, oxidative stress and amino acid metabolism. Although the relationship between autophagy and p53 is quite complicated, and has not been well elucidated, p53 may underlie key aspects of metabolism and cancer biology. Thus, understanding the novel functions of p53 may allow us to develop new anticancer therapeutic approaches.
Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ∼95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours.
We recently found that repeated application of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or recombinant TRAIL proteins to TRAIL-susceptible cancer cells resulted in selection and expansion of TRAIL-resistant cells. Overcoming this acquired resistance to TRAIL is desirable for TRAIL-mediated cancer therapy. Here we demonstrate that several chemotherapeutic agents, including 5-fluorouracil (5-FU) and mitomycin, and calpain inhibitor I, an NFkappaB inhibitor, can overcome acquired resistance to TRAIL in DLD1 colon cancer cells. The combination of TRAIL (approved gene symbol TNFSF10) gene therapy and 5-FU enhanced tumor suppression in vivo in nude mice bearing subcutaneous tumors established from TRAIL-resistant colon cancer cells. Whereas treatment with the combination of TRAIL and 5-FU or mitomycin led to enhanced activation of caspase-3, the combination of TRAIL and calpain inhibitor I resulted in enhanced activation of both caspase-8 and caspase-3. Moreover, mitomycin, but not 5-FU or calpain inhibitor I, induced overexpression of the BAX gene, which was correlated with enhanced TRAIL-induced cell killing in TRAIL-resistant DLD1 cells. Together, these results suggest that acquired resistance to TRAIL can be overcome by different mechanisms and that combinations of TRAIL gene therapy and chemotherapy may be a useful approach for cancer treatment.
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