Retinal Targets ALDH Positive Cancer Stem Cell and Alters the Phenotype of Highly Metastatic Osteosarcoma Cells

Abstract

Aldehyde dehydrogenase (ALDH) is a cancer stem cell marker. Retinoic acid has antitumor properties, including the induction of apoptosis and inhibition of proliferation. Retinal, the precursor of retinoic acid, can be oxidized to retinoic acid by dehydrogenases, including ALDH. We hypothesized that retinal could potentially be transformed to retinoic acid with higher efficiency by cancer stem cells, due to the higher ALDH activity. We previously observed that ALDH activity is greater in highly metastatic K7M2 osteosarcoma (OS) cells than in nonmetastatic K12 OS cells. We also demonstrated that ALDH activity correlates with clinical metastases in bone sarcoma patients, suggesting that ALDH may be a therapeutic target specific to cells with high metastatic potential. Our current results demonstrated that retinal preferentially affected the phenotypes of ALDH-high K7M2 cells in contrast to ALDH-low K12 cells, which could be mediated by the more efficient transformation of retinal to retinoic acid by ALDH in K7M2 cells. Retinal treatment of highly metastatic K7M2 cells decreased their proliferation, invasion capacity, and resistance to oxidative stress. Retinal altered the expression of metastasis-related genes. These observations indicate that retinal may be used to specifically target metastatic cancer stem cells in OS.

Novel molecular insights and new therapeutic strategies in osteosarcoma

“…High ALDH has been previously applied as a marker for identifying tumorigenic cell fractions in many kinds of malignancies and reveled to be associated with tumorigenic cell fractions (higher levels of tumorigenicity), differentiation and self-renewal as well as metastatic potential in OS cell lines [ 4 , 30 ]. ALDH activity is upregulated in cancer stem cells, where is shown as a marker for cancer stem cells [ 31 – 33 ]. The inhibition of ALDH activity by applying disulfiram has led to a reduction in cell proliferation, consequently, it suggests direct targeting of CSC genotypes [ 24 , 34 ].…”

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

“…ALDH-high K7M2 cells exhibited a greater increase in apoptosis compared to ALDH-low cells. Additionally, RT-PCR demonstrated that retinal treatment resulted in downregulation of various genes involved in cell proliferation and cell survival in a dose-dependent manner [49]. This would suggest that retinal can efectively be used as a cellular "Trojan Horse" of sorts to speciically target OS cells, as the very ALDH-rich nature that is crucial to their metastatic potential leads to their willful acceptance and rapid metabolism of retinal, leading ultimately to their demise.…”

“…RA has been shown to inhibit proliferation of malignant tumors and induce apoptosis and differentiation [32,[49][50][51][52][53]. Most notably, all-trans-retinoic acid (ATRA) is an efective treatment Osteosarcoma -Biology, Behavior and Mechanismsfor acute promyelocytic leukemia (APL) and has been shown to result in complete remission [50,54].…”

“…RA is derived from ATRA by the action of ALDHs. Since ALDH is often speciically upregulated in CSCs, clever design can exploit this pathway for tumor suppression [49].…”

“…In mouse model studies, the highly metastatic K7M2 OS cells seem to be preferentially targeted by RA [49]. The role of retinal in decreasing cell proliferation and cell survival was demonstrated by exposing cells to oxidative stress in the form of hydrogen peroxide.…”