A small natural molecule CADPE kills residual colorectal cancer cells by inhibiting key transcription factors and translation initiation factors

Abstract

Residual disease is the major cause for colorectal cancer (CRC) relapse. Herein, we explore whether and how a natural molecule CADPE killed heterogenic populations in a panel of CRC cell lines with KRAS/BRAF mutations that are natively resistant to EGFR- or VEGFR-targeted therapy, without sparing persistent cells, a reservoir of the disease relapse. Results showed that CADPE killed the tumor bulk and residual cells in the panel of CRC cell lines, rapidly inactivated c-Myc, STAT3, and NF-κB, and then decreased the protein levels of key signaling molecules for CRC, such as β-catenin, Notch1, and the nodes of mTOR pathways; eukaryotic translation initiation factors (eIF4F); anti-apoptotic proteins (Bcl-xl, Mcl-1, and survivin); and stemness-supporting molecules (CD133, Bim-1, and VEGF). In terms of mechanism of action, concurrent downregulation of Mcl-1, Bcl-xl, and survivin was necessary for CADPE to kill CRC bulk cells, while additional depletion of CD133 and VEGF proteins was required for killing the residual CRC cells. Moreover, the disabled c-Myc, STAT3, NF-κB, and eIF4F were associated with the broadly decreased levels of anti-apoptosis proteins and pro-stemness proteins. Consistently, CADPE suppressed CRC tumor growth associated with robust apoptosis and depleted levels of c-Myc, STAT3, NF-κB, eIF4F, anti-apoptotic proteins, and pro-stemness proteins. Our findings showed the promise of CADPE for treating CRC and suggested a rational polytherapy that disables c-Myc, STAT3, NF-κB, and eIF4F for killing CRC residual disease.

LncRNA WWTR1-AS1 upregulates Notch3 through miR-136 to increase cancer cell stemness in cervical squamous cell carcinoma

“…S3 A). Compared with the control group (C group), overexpression of WWTR1-AS1 and Notch3 was observed to enhance the stemness of CSCC cells, reflected by the increase in the percentage of CD133 + cells [ 18 , 19 ]. The overexpression of miR-136 led to a reduction in CSCC cell stemness and counteracted the effects of WWTR1-AS1 and Notch3 overexpression on CSCC cell stemness.…”

MiR-323a-3p Inhibits Tumor Growth and Gefitinib Resistance Acquisition by Targeting EGFR/ErbB3 in Colorectal Cancer

“…Mutations in Kras, BRAF, BIM polymorphism de ciency and EML4-ALK fusion gene mutations are the primary resistance mechanisms against EGFR inhibitors (33). In a PDX model of mouse lung adenocarcinoma, Emilio's team found that EGFR signaling is involved in K-Ras-driven lung tumorigenesis in both humans and mice.…”