Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines

Abstract

Background: TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. Results: Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance. Conclusion: Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging. Methods: We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

“…DDR1 has five isoforms, including DDR1a‐e, while DDR2 only has one isoform 19 . The differences between these isoforms are caused by the alternative splicing of mRNA in the catalytic region of the intracellular KD 21 . Among all subtypes of DDR1, DDR1d and DDR1e are kinase‐deficient due to the lack of a complete reading frame (Figure 1).…”

“…Typical RTK activation is triggered within a few seconds after binding to a ligand 23 . However, the phosphorylation process of DDR is remarkably slow, taking several hours to achieve full activation 17,21 . Previously, it was thought that DDR could only be activated by collagen binding.…”

“…In breast cancer, colon carcinoma, and osteosarcoma cell lines, DDR1 promotes cell survival through the Ras/Raf/mitogen‐activated protein kinase pathways under genotoxic stress 43 . In KRAS‐mutated lung cancer, DDR1 facilitates lung cancer cell proliferation by activating the phosphatidylinositol 3‐kinase/protein kinase B signaling pathways 21,44 . In colon cancer cells, DDR1 can activate Notch 1 to upregulate the expression of pro–survival genes Hes1 and Hey2 45 .…”

“…19 The differences between these isoforms are caused by the alternative splicing of mRNA in the catalytic region of the intracellular KD. 21 Among all subtypes of DDR1, DDR1d and DDR1e are kinase-deficient due to the lack of a complete reading frame ( Figure 1). 22 Unlike other RTK, DDR are activated by different types of collagen instead of soluble growth factors.…”

“…23 However, the phosphorylation process of DDR is remarkably slow, taking several hours to achieve full activation. 17,21 Previously, it was thought that DDR could only be activated by collagen binding. In recent years, researchers have found a novel activation model of DDR by interaction with the IIGF system.…”