Morin‐dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW‐PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in anApc‐driven model of colon cancer

LMW‐PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW‐PTP expression in Pirc rats (F344/NTac‐Apc am1137 ), genetically prone to CRC and resistant to apoptosis. In the morphologically normal mucosa (NM) of Pirc rats, a dramatic over‐expression of LMW‐PTP was found compared to wt rats (about 60 times higher). Moreover, LMW‐PTP levels further increase in spontaneously developed Pirc colon tumors. To understand if and how LMW‐PTP affects resistance to apoptosis, we studied CRC cell lines, sensitive (HT29 and HCT‐116), or resistant (HT29R, HCT116R) to 5‐Fluorouracil (5‐FU): resistant cells over‐express LMW‐PTP. When resistant cells were challenged with morin, a polyphenol inhibiting LMW‐PTP, a fast and dose‐related down‐regulation of LMW‐PTP was observed. 5‐FU and morin co‐treatment dramatically decreased cell viability, increased apoptosis, and significantly impaired self‐renewal ability of all the cancer cell lines we have studied. Similarly, we observed that, in Pirc rats, one‐week morin administration (50 mg/kg) down‐regulated LMW‐PTP and restored the apoptotic response to 5‐FU in the NM. Finally, administration of morin for a longer period led to a significant reduction in colon precancerous lesions, together with a down‐regulation of LMW‐PTP. Taken together, these results document the involvement of LMW‐PTP in the process of CRC in vitro and in vivo. Morin treatment may be envisaged as a system to increase the sensitivity to chemotherapy and to prevent carcinogenesis.