| Summary: | 碩士 === 國立中興大學 === 生物醫學研究所 === 107 === In Taiwan, colorectal cancer shows the highest cancer incidence and is the third cause of cancer mortality in both genders. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in colorectal cancer was found to mediate malignant transformation and associated with poor prognosis. Hispolon is an anticancer component of the medicinal fungus Phellinus linteus and known to induce cell cycle arrest and apoptosis. Methoxyhispolon methyl ether (MHME) is one of the Hispolon analogs with unknown effect and mechanisms on colorectal cancer. In the present study, we demonstrated for the first time that MHME potently induced cytotoxicity and apoptosis against several human colorectal cell lines with stronger potency than Hispolon did, but its cytotoxicity to normal human colon epithelial cells is limited. Also, we discovered that MHME suppressed the constitutive activation of STAT3. Moreover, it is noteworthy that overexpression of dominantly active STAT3 thwarted MHME-induced apoptosis, proving that inhibition of STAT3 activation is required for MHME-mediated anti-colorectal cancer activity. We also found that MHME can effectively inhibit the activity of JAK2 and SRC in the upstream of STAT3, and SRC overexpression inhibited MHME-induced STAT3 activation and apoptosis, confirming that MHME promotes apoptosis by inhibiting SRC activity and thereby inhibiting STAT3 activity. Furthermore, we revealed that MHME reduced the expression level of STAT3 target gene BCL-2, which was counteracted by constitutive activation of STAT3. Importantly, BCL-2 overexpression inhibited MHME-induced apoptosis, thus confirming that BCL-2 downregulation is responsible for the proapoptotic effect of MHME on colorectal cancers. In addition to inducing apoptosis, we revealed that MHME treatment led to a G2/M cell cycle arrest. In summary, our results support that MHME induces cell apoptosis by suppressing the JAK2/SRC-STAT3-BCL-2 survival pathway and also inhibits cell proliferation through arresting the cell cycle at the G2/M phase in colorectal cancer cell lines.
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