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2
,
*
Department of Microbiology & Immunology,
Department of Biochemistry and
Fels Institute of Cancer Research & Molecular Biology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140
2To whom correspondence should be addressed. E-mail: sopranok{at}astro.temple.edu.
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ABSTRACT |
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 TOP ABSTRACT Oral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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-selective retinoids SR 11254 and SR 11389. In contrast, stable oral SCC clones that constitutively overexpressed the mouse dominant negative mutant, RAR-ß (R269Q), were shown to exhibit reduced RAR/RXR transcriptional transactivation function and reduced sensitivity to growth inhibition by RA, SR 11254 and SR 11389. Likewise, the RAR- antagonist SR 11253 was found to block the ability of SR 11254 and SR 11389 to inhibit SCC growth. These results indicate that modulation of RAR function through the use of either an RAR--selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCCs to retinoids.
KEY WORDS: • oral cancer • synthetic retinoids • all-trans retinoic acid • oral squamous cell carcinoma cells • dominant negative RAR • RAR antagonists • RAR/RXR • receptor-selective synthetic retinoids
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Oral cancer |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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40,000 Americans are afflicted with oral cancer (1
). It is the sixth most common cancer for both sexes in the overall population of the United States (2
). More than 90% of the oral cancers are squamous cell carcinomas (SCCs),3 and a significant number of these occur in the oral cavity (2
). Unfortunately, the overall 5-y survival rate for patients diagnosed with oral cancer is only 50%, a percentage that has not changed significantly over the past two decades (3
). The number of deaths attributed to oral cancer exceeds that for cervical cancer, malignant melanoma and Hodgkin’s disease. In addition to its high mortality rate, oral SCC also has a major functional and cosmetic impact as a result of its location. Clearly there is a need to develop new strategies for the successful treatment of this disease. As will be discussed, retinoids have been used successfully in the treatment oral SCC. However, for reasons yet to be understood, not all oral cancers are responsive to retinoid treatment. Understanding the mechanism by which retinoids act to inhibit oral SCC growth will provide important and valuable information for the development of future oral cancer chemotherapeutic strategies. |
Retinoids and cancer |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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–6
). Retinoids have been demonstrated to inhibit development of a number of different types of tumors (e.g., epithelial tumors associated with the skin, respiratory tract, stomach and mammary gland) (7
,8
) and to inhibit the growth of a variety of neoplastically transformed cells (e.g., HL-60 promyelocytic leukemia cells, F9 teratocarcinoma cells and malignant melanoma cells) by differentiating these cells (9
–11
), suggesting their potential role as a cancer chemotherapeutic agent. More recently, the usefulness of retinoids as cancer therapeutic agents has been recognized by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program. NCI, in cooperation with Hoffman-LaRoche Pharmaceutical Company, has obtained an Investigational New Drug status for the therapeutic use of RA. Phase I studies to define maximally tolerated doses and pharmacokinetics of daily dosage schemes are now being conducted in patients with solid tumors (for review, see Ref. 12
).
Studies from a number of laboratories including our own have analyzed the ability of retinoic acid (RA) to inhibit the growth of human tumor cell lines (13
–28
). RA treatment was found to reduce DNA synthesis, induce morphological changes, prolong cell doubling time and reduce saturation density and colony formation in soft agar assays. In virtually all of these cases, retinoid suppression of growth does not involve the death of tumor cells but rather their arrest during the G1 stage of the cell cycle (14
).
It should be noted that although retinoids efficiently inhibit the growth of many types of epithelial tumors, no single common mechanism of action has been identified. Even cancers as closely related as breast and ovarian exhibit unique targets on which retinoids act to inhibit cell growth.
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Retinoids and SCC |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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,30
). The ability of retinoids to inhibit the growth of SCC lines has been known for some time (22
–28
). Recently, retinoids have been successfully used in vivo to prevent the progression of preneoplastic oral, bronchial and head and neck lesions to frank malignant tumors (31
–34
). More specifically, treatment with 13-cis RA (isotretinoin) has been shown to significantly reduce the appearance of head and neck squamous carcinomas in patients at high risk for development of second primary tumors (32
). As a result of these encouraging studies, several clinical trials have been initiated to investigate the ability of retinoids to reverse oral premalignancy (33
). Retinoids have also been successfully used in the treatment of SCCs. 13-cis RA in combination with interferon 
has been successfully used to treat SCCs of the cervix and skin (35
). Clearly, experimental evidence is strong in support of the important role of retinoids in both the chemoprevention and treatment of oral SCCs. Although the success of retinoid chemotherapy for oral cancer is clearly documented, the exact molecular mechanism by which retinoids alter growth in oral SCCs remains to be determined. |
Retinoic acid receptors and retinoid X receptors |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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). Analysis of the deduced amino acid sequence has demonstrated that these receptors are quite homologous to the steroid/thyroid hormone receptors. Each contains a highly conserved DNA binding domain (C) and a well-conserved ligand binding domain (E) and three or four additional domains that are not as well conserved (A, B, D and F). The RARs and RXRs have each been demonstrated to bind RA and to alter the rate of transcription of specific genes via a retinoic acid response element (RARE) within the promoter of genes. Tremendous effort on the part of many laboratories is presently being directed to identify the responsive genes. It has therefore become clear that RA can regulate gene expression via these ligand-dependent nuclear receptors in a manner similar to steroid hormones, thyroid hormone and vitamin D.
The RARs have a high affinity binding site for all-trans and 9-cis RA. Three types of RARs have been identified (RAR-, RAR-ß and RAR-) with homologous but slightly different RA binding domains (for review, see Ref. 36
). Transactivation assays and retinoid binding assays with RAR-, RAR-ß and RAR- have shown that each RAR has a different affinity for RA and a number of RA analogs. Seven isoforms of RAR- and RAR- and four isoforms of RAR-ß have been identified. The isoforms of each RAR differ in amino-terminal domains A and B; however, domains C through F, including the ligand binding domain, are identical. Analysis of the pattern of expression of each of the RARs and their respective isoforms suggests that each displays an unique pattern of expression within tissues of the developing embryo and the adult (37
). Taken together these data suggest that each of the RARs and their respective isoforms may have unique functions.
RXR was initially identified as an orphan receptor that required 10- to 100-fold higher concentrations of all-trans RA than the RARs in transactivation assays (for review, see Ref. 36
). Recently it was shown that a natural ligand for RXR is an isomer of all-trans RA called 9-cis RA (38
,39
). In addition, three major forms of RXR have now been identified, called RXR-, RXR-ß and RXR-; however, at present we do not know the relative affinity of each of the RXRs for retinoid. Furthermore, each of the RXRs displays a unique pattern of expression in the developing embryo and the adult. Most recently, RXRs have been implicated in modifying transcription by forming heterodimers with the RARs, thyroid hormone receptor and vitamin D receptor.
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RARs, RXRs and cancer |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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and RAR-ß genes have been found to be associated with two different types of cancer. In acute promyelocytic leukemia the RAR- gene has been demonstrated to be translocated from chromosome 17 to the myl locus on chromosome 15, resulting in a myl/RAR- fusion protein. Treatment with all-trans RA and potentially other less toxic retinoids shows great promise for the remission of this leukemia in patients (40
). The RAR-ß cDNA was originally identified in a hepatocellular carcinoma. It was found that the hepatitis B virus had integrated within the human liver DNA near what is now known to be the RAR-ß gene, causing inappropriate expression of this gene within the liver cells presumably resulting in the hepatocarcinogenesis (41
). |
RARs and RXRs and oral SCC |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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,43
) compared the expression of each of the RAR and RXR subtypes in a variety of epithelial cells obtained from the oral cavity, including cultured human oral and epidermal SCCs, normal human epithelial cells and benign, hyperplastic and hyperkeratotic lesions. These investigators found a dramatic decrease in the expression of RAR-ß in the SCC lines. Interestingly, no alteration in the structure or arrangement of the RAR-ß gene could be detected in the SCC DNA by Southern blotting. This observation was confirmed and extended to biopsy material by Lotan and colleagues (34
,44
). Using in situ hybridization, these investigators found that RAR-, RXR- and RXR-ß levels were comparable in normal, preneoplastic and malignant lesions of the oral cavity. However, RAR-ß mRNA was detected in only about one third of the SCC lesions and one half of the premalignant lesions compared with 70% of the adjacent normal tissue. Interestingly, treatment of patients with 13-cis RA for a period of 3 mo resulted in an increase in RAR-ß expression and a coincident positive clinical response.
Similar studies that have analyzed RAR- expression in oral SCC show that this RAR subtype is generally not lost in SCC but is frequently reduced (45
,46
). Moreover, Monzon et al. (47
) identified an SCC line, designated SCC 12F which exhibited reduced differentiation in response to retinoic acid and a corresponding significant reduction in RAR- expression compared to other SCC lines. Oridate et al. (48
) used antisense and overexpression approaches to study the effect of modulating RAR- levels on the growth of a head and neck SCC line (SqCC/Y1). Recently, we have published studies that used RAR-selective retinoids and dominant negative pan-RAR mutants to show that RAR- plays an important role in mediating the inhibition of SCC growth by retinoids (13
).
The overall goal of this project was to elucidate the precise role of the nuclear retinoic acid receptors in mediating the growth response of human oral SCCs to RA. More specifically, we wanted to investigate a number of potential mechanisms by which RARs and RXRs might act to inhibit growth and induce differentiation in oral SCCs. To achieve this goal we set out to determine if retinoid-dependent growth suppression of oral SCCs can be modulated by changing the RAR profile in these cells via altering the expression, overall composition and/or function of individual RARs, RXRs or interacting cofactors.
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All-trans RA alters the growth of oral SCC lines |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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.
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Overexpression of dominant negative mutant RAR-ß2(R269Q) alters the sensitivity of SCC-25 cells to all-trans RA-mediated growth inhibition |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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) and alters the growth sensitivity of ovarian carcinoma cells to retinoids (14
–17
), we next determined the effects of downregulation of RAR/RXR function on all-trans RA-induced growth inhibition of SCC-25 cells. SCC-25 cells overexpressing mutant RAR-ß2(R269Q) or MSCVpac vector transduced SCC-25 cells were treated with all-trans RA at concentrations ranging from 10-10 to 10-6 M. Control cultures were treated with an equal volume of ethanol. MTT assay was performed on day 7 after treatment. Figure 2
A shows that the concentration of all-trans RA required to reduce growth of SCC-25 cells carrying the empty vector by 50% (ID50) was 5 x 10-8 M. In contrast the ID50 for the SCC-25 cells overexpressing mutant RAR-ß2(R269Q) was 8 x 10-6 M. Thus, reduction of functional RAR/RXR significantly altered the growth inhibitory response of SCC-25 cells to all-trans RA.
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10–15% in SCC-25 cells overexpressing mutant RAR-ß2(R269Q), compared with 60–70% inhibition in the MSCVpac vector transduced control SCC-25 cells (Fig. 2B)
. Clearly, modulation of RAR/RXR function through the use of a pan-RAR dominant negative mutant significantly altered the growth inhibitory response of SCC-25 cells to all-trans RA. |
Synthetic RAR--selective retinoids inhibit growth of SCC-25 cells
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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in mediating retinoid growth responses in oral SCCs (48
), we next examined the growth inhibitory activity of RAR--selective retinoids. SCC-25 cells were treated with synthetic retinoids (SR11253, SR11254 or SR11389) at a concentration of 10-6 M for 7 d. Direct cell counting was performed after treatment for 1, 3, 5 and 7 d. The results show that the synthetic RAR--selective agonists SR11254 and SR11389 significantly inhibited the growth of SCC-25 cells, whereas the RAR--selective antagonist SR11253 alone did not significantly change the growth of SCC-25 cells (Fig. 3
). It should be noted, however, that retinoid-mediated growth inhibition was significantly reduced when SCC-25 cells were treated simultaneously with all-trans RA or an RAR- agonist and the RAR- anatagonist (data not shown).
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Overexpressing dominant negative mutant RAR-ß2(R269Q) alters the sensitivity of SCC-25 cells to synthetic retinoid-mediated growth inhibition |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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,49
), we next wanted to determine the effect of synthetic RAR--selective retinoids on the growth of SCC-25 cells overexpressing mutant RAR-ß2(R269).
To determine the dose-dependent effects of synthetic RAR--selective agonists on the mutant cells, SCC-25 cells overexpressing mutant RAR-ß2(R269Q) or MSCVpac vector transduced SCC-25 cells were treated with either SR11254 or SR11389 at concentrations ranging from 10-10 to 10-7 M. Control cultures were treated with an equal volume of ethanol. Cell counting assay was performed on day 5. SCC-25 cells overexpressing mutant RAR-ß2(R269Q) were shown to have reduced sensitivity to growth inhibition after treatment for 5 d with either synthetic RAR- agonist retinoid SR11254 or SR11389 at concentrations ranging from 10-10 to 10-7 M. These results shown in Figure 4
clearly indicate that RAR- plays an important role in retinoid-mediated growth inhibition of SCC-25 cells.
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CONCLUSIONS |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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in particular. Because RARs are transcriptional transactivators, the next step in the elucidation of the molecular mechanism by which retinoids inhibit oral SCC growth involves the identification of molecular targets whose expression is regulated by RAR/RXR activation. Retinoids may induce tumor cells to differentiate or undergo apoptosis (50
,51
). However, we found that there was no morphological or molecular evidence suggesting that all-trans RA-treated SCC-25 cells undergo differentiation or apoptosis (data not shown). Alternatively, because retinoids have been shown in this as well as other cancer models to induce a block in the G1 stage of the cell cycle (13
,14
), the best candidate genes for mediators of retinoid growth suppression are likely to be those that regulate cell cycle progression during G1 (52
–54
).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 3 Abbreviations used: RA, retinoic acid; RAR, retinoic acid receptors; RXR, retinoid-x-receptors; SCC, squamous cell carcinoma; SR, selective retinoid.
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LITERATURE CITED |
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TOPABSTRACTOral cancerRetinoids and cancerRetinoids and SCCRetinoic acid receptors and...RARs, RXRs and cancerRARs and RXRs and...All-trans RA alters the...Overexpression of dominant...Synthetic RAR-{gamma}-selective...Overexpressing dominant negative...CONCLUSIONSLITERATURE CITED |
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