Abstract
Cancer stem cells (CSCs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (CRC). As current chemotherapy doesn’t eliminate CSCs completely, there is a need to identify novel agents to target them. We investigated the effects of cucurbitacin B (C-B) or I (C-I), a natural compound that exists in edible plants (bitter melons, cucumbers, pumpkins and zucchini), against CRC. C-B or C-I inhibited proliferation, clonogenicity, induced G2/M cell-cycle arrest and caspase-mediated-apoptosis of CRC cells. C-B or C-I suppressed colonosphere formation and inhibited expression of CD44, DCLK1 and LGR5. These compounds inhibited notch signaling by reducing the expression of Notch 1–4 receptors, their ligands (Jagged 1-2, DLL1,3,4), γ-secretase complex proteins (Presenilin 1, Nicastrin), and downstream target Hes-1. Molecular docking showed that C-B or C-I binds to the ankyrin domain of Notch receptor, which was confirmed using the cellular thermal shift assay. Finally, C-B or C-I inhibited tumor xenograft growth in nude mice and decreased the expression of CSC-markers and notch signaling proteins in tumor tissues. Together, our study suggests that C-B and C-I inhibit colon cancer growth by inhibiting Notch signaling pathway.
Highlights
Cancer stem cells (CSCs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (CRC)
The presence of cancer stem cells (CSCs) that are responsible for drug resistance and cancer recurrence remains the major hurdle in the treatment of CRC5,6
We studied the effects of cucurbitacin-B (C-B) and -I (C-I), phytochemicals because it is present in bitter melon
Summary
Cancer stem cells (CSCs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (CRC). Cancer stem cells (CSCs) are rare in number and possess the ability to self-renew with the capacity to generate a tumor[4,5] They develop chemo- and radio-resistance, contributing to tumor progression and recurrence. Targeting the Notch signaling pathway may be an effective mechanism to eliminate colon CSCs. Recently, phytochemicals, which are naturally occurring compounds isolated from plants, have been reported to target CSCs and their signaling pathways[4,5]. C-I has been reported to inhibit self-renewal of CD133+cells in thyroid and lung cancer, inhibit STAT3 phosphorylation enhancing chemo and radiosensitivity in medulloblastoma-derived CSCs, and suppress stem-like properties and induce apoptosis in head and neck cancer-derived CD44+-ALDH+cells[26]. For the first time, we demonstrate the potential of C-B and C-I compounds to inhibit colon CSCs through the Notch-signaling pathway
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