Role of OCT-3 on metformin action in oral carcinogenesis

《Oct-3在二甲双胍在口腔癌发生中的作用》 这项建议的长期目标是确定将从使用 二甲双胍或相关的双胍类化合物在口腔癌预防和治疗中的应用。在美国，大约有1 每天每小时都有人死于与口腔癌相关的并发症，主要是口腔癌 鳞癌(OSCC)。不幸的是，口腔鳞状细胞癌患者存活率的改善仍然存在。 几十年来一直没有改变。多灶性潜在恶性不典型增生的晚期诊断和“野生性癌变” 病变或继发性原发口腔鳞癌是影响标准治疗的主要因素。在这方面，龙- “高危”口腔癌前病变的长期化学预防靶向可能提供一个很好的控制机会 口腔鳞状细胞癌的发展和进展。我们最近报道了FDA批准的双胍类药物二甲双胍 作为2型糖尿病的一线治疗，显著防止致癌物诱导的口腔转化 免疫活性小鼠口腔鳞状细胞癌癌前病变。尽管取得了重大进展，但一个关键的 一个仍然难以捉摸的问题是二甲双胍是直接作用于肿瘤细胞，还是影响癌症的发展 通过控制瘤外部位的荷尔蒙反应。这一认识上的差距在临床上具有重大意义 因为，作为一种高度亲水性的阳离子药物，二甲双胍在细胞内的摄取依赖于组织- 一组多特异性细胞膜有机阳离子转运体(OCTs)促进的特殊机制 属于溶质载体22A(SLC22A)基因家族。虽然，众所周知，Oct-1，Oct-2和Oct-3 介导不同正常组织对二甲双胍的摄取，目前尚不清楚OCT在 二甲双胍或其他相关双胍的抗肿瘤作用。我们的初步研究表明，10月3日是 二甲双胍在口腔癌发生中的摄取转运体。我们在口腔鳞癌细胞系中发现了可变的Oct-3表达 来源于人类口腔癌前病变和口腔鳞癌肿瘤。有趣的是，Oct-3的强表达是 常见于口腔异型增生和分化较好的口腔鳞癌，但在 不典型的、分化较低的口腔鳞状细胞癌。这些结果提示OCT-3的表达与其程度有关 ，并指出这种以前未知的联系是一种潜在的机制 口腔癌变过程中对二甲双胍的耐药性。相比之下，苯乙双胍，一种更疏水性的双胍， 似乎较少依赖Oct-3介导的摄取，可能是比已建立的靶点更好的替代方案， OCT-3阴性口腔鳞癌。通过体外和体内的方法，我们将检验总体假设 二甲双胍或相关双胍如苯福明对肿瘤生长的抑制作用依赖于Oct-3摄取 口腔癌原发灶的活动性。提出了三个具体目标。目标1将定义 OCT-3在二甲双胍诱导口腔鳞癌细胞增殖中的作用目标2将确定 Oct-3对二甲双胍在口腔癌发生中的化学预防作用目标3将确定Oct-3的依赖性 用于口腔癌变过程中苯乙双胍的抗肿瘤活性。通过阐明双胍类化合物的作用机制 对于摄取和活性，我们预计拟议研究的结果可能最终影响选择 最适合的患者谁可以受益于这些药物在口腔癌的化学预防和治疗。

"Role of OCT-3 on metformin action in oral carcinogenesis" The long-term goal of this proposal is to identify the target patient population who will benefit from the use of metformin, or related biguanides, in oral cancer prevention and treatment. In the United States, roughly one person dies every hour of each day because of complications associated with oral cancer, mainly oral squamous cell carcinoma (OSCC). Unfortunately, improvements in OSCC patient survival rates have remained unchanged for decades. Late diagnosis and "field cancerization" with multifocal potentially malignant dysplastic lesions or secondary primary OSCCs are major factors compromising standard treatments. In this regard, long- term chemopreventive targeting of "at risk" oral premalignant lesions may offer a great opportunity to control OSCC development and progression. We recently reported that metformin, a FDA-approved biguanide used as first-line treatment for type 2 diabetes, significantly prevented the conversion of carcinogen-induced oral premalignant lesions into OSCC tumors in immunocompetent mice. Despite significant progress, a critical issue that remains elusive is whether metformin acts directly on the tumor cells, or affects cancer development by controlling hormonal responses at extratumoral sites. This gap in knowledge holds significant clinical implications because, as a highly hydrophilic cationic drug, metformin intracellular uptake relies on tissue- specific mechanisms facilitated by a group of polyspecific cell membrane organic cation transporters (OCTs) belonging to the solute carrier 22A (SLC22A) gene family. Although, it is known that OCT-1, OCT-2 and OCT-3 mediate metformin uptake in different normal tissues, it is still unclear which role OCTs play on the antineoplastic effects of metformin, or other related biguanides. Our preliminary studies point to OCT-3 as the uptake transporter of metformin in oral carcinogenesis. We found variable OCT-3 expression in OSCC cell lines derived from human oral premalignant lesions and OSCC tumors. Interestingly, strong OCT-3 expression was commonly observed in oral dysplasias and well-differentiated OSCC, but progressively declined in more atypical, less differentiated OSCC tumors. These results suggest that OCT-3 expression is linked to the degree of tumor cell differentiation, and points to this previously unidentified association as a potential mechanism of resistance to metformin in oral carcinogenesis. In contrast, phenformin, a more hydrophobic biguanide, appears to be less dependent on OCT-3-mediated uptake and likely a better alternative to target established, OCT-3 negative OSCC tumors. Through in vitro and in vivo approaches, we will test the overall hypothesis that tumor growth inhibition by metformin or related biguanides such as phenformin is dependent on OCT-3 uptake activity at the primary site of oral carcinogenesis. Three specific aims are proposed. Aim 1 will define the contribution of OCT-3 on OSCC cell proliferation in response to metformin. Aim 2 will determine the impact of OCT-3 on metformin chemopreventive action in oral carcinogenesis. Aim 3 will identify dependence of OCT-3 for the antineoplastic activity of phenformin in oral carcinogenesis. By elucidating mechanisms of biguanide uptake and activity, we envision that the outcomes of the proposed studies may ultimately impact the selection of the most suitable patients who can benefit from these drugs in oral cancer chemoprevention and treatment.