Cancerous inhibitor of protein phosphatase 2A (CIP2A) an endogenous inhibitor of protein phosphatase 2A (PP2A), which can promote proliferation and transformation of several cancer types, has been shown to be a target for tumor therapy. The present study investigated the effects and underlying mechanisms of action of a novel natural compound, ethoxysanguinarine (Eth), on colorectal cancer (CRC) cells. MTT assay and flow cytometric assay found that Eth inhibited the viability and induced the apoptosis of the CRC cells. The inhibition of viability and activation of apoptosis was mediated through the Eth-induced decrease in CIP2A expression. Knockdown of CIP2A by RNA interference sensitized, whereas overexpression of CIP2A antagonized, Eth-induced viability inhibition and apoptosis. Furthermore, western blot analysis suggested that Eth inhibited phosphorylation of CIP2A downstream molecule protein kinase B via the activation of PP2A. CRC xenograft tests also confirmed the antitumor effect of Eth in vivo. These results advance our understanding of Eth-induced viability inhibition and apoptosis, implying the requirement for further investigation of Eth as a CIP2A inhibitor for cancer therapies.

Pain and depression comorbidity affect the patients’ both physical and mental health and quality of life seriously. The comorbid depressive symptoms in cancer pain severely affect the recognition and treatment of pain. Similarly, cancer pain patients with depression are inclined toward more despair and greater impairment. The mechanisms responsible for the comorbid depressive symptoms in cancer induced bone pain have not been fully delineated and the currently available therapeutics for this pathological pain is relatively limited. In the present study, we observed that carcinoma cells implantation induced pain and depression comorbidity resulted in the upregulation of major histocompatibility complex class I (MHC-I) in hippocampus associated with the activation of TREM2/DAP12-mediated microglial signaling pathways. These observations were reversed by a lentiviral vector harboring RNA interference sequence targeting MHC-I injected into the hippocampus of tumor bearing mice. Together, these results suggest that MHC-I involves in the cancer induced bone pain and depression comorbidity through regulating the TREM2/DAP12-mediated signals in microglia of hippocampus. Suppression of MHC-I could be a therapeutic target for cancer induced bone pain.

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