PDLIM2 as a cancer and chemosensitizing target

描述(申请人提供)：化疗仍然是许多癌症的标准一线治疗方法，包括肺癌，肺癌是癌症死亡的主要原因，仅在美国每年就有大约16万人死亡。然而，由于癌细胞的内在和获得性耐药，目前化疗的益处非常有限。我们研究的长期目标是了解肿瘤发生和化疗耐药的潜在机制，并将这种理解转化为新的方法，通过建立新的有效疗法和/或启动癌细胞对当前治疗药物的反应来提高癌症治愈率。为此，我们最近发现PDLIM2是一种在肺部表达水平最高的PDZ-LIM结构域蛋白，可抑制肺癌和其他几种癌症类型，如成人T细胞白血病/淋巴瘤(ATL)、乳腺癌和结肠癌。我们发现，在这些癌细胞中，PDLIM2的表达受到表观遗传学的抑制，并且PDLIM2的重组可以阻止它们的致瘤作用。此外，PDLIM2缺乏使小鼠易患自发性和诱发性癌症，尤其是肺癌。值得注意的是，PDLIM2表达的抑制与肺癌的化疗耐药有关，表观遗传药物5-aza-DC需要重新诱导PDLIM2才能抑制多药耐药肺癌细胞的生长并对化疗药物卡铂产生反应。机制研究表明，PDLIM2作为一种泛素E3连接酶选择性地降解核(激活)的NF-κB RelA(也称为P65)，P65是一种转录因子，已被认为在包括ATL、乳腺癌、结肠癌和肺癌在内的多种人类癌症的发生和治疗耐药中发挥了致病作用。基于这些创新的发现，我们假设PDLIM2抑制导致结构性的NFκB激活，这反过来又有助于癌症的发病和治疗抵抗。在这一应用中，我们的目标是(1)确定PDLIM2在肺癌中表达下调的分子机制；(2)阐明PDLIM2在肺癌发生发展中的机制；(3)研究PDLIM2在肺癌化疗敏感性和治疗中的作用和机制。这些研究具有创新性和重要意义，因为它们将极大地增加我们对肺癌发生和化疗耐药的理解，并可能形成一类新的基于PDLIM2的表观遗传学方法，作为肺癌预防和治疗的主要或辅助治疗。特别是，临床试验表明，阻断NF-κB的激活对 由于核因子-κB在人体生理学中的重要性，使用“经典的”核因子-κB抑制剂进行癌症治疗。然而，PDLIM2通过终止NF-κB的激活来阻止病理性的而不是生理性的NF-κB的激活。一直以来，PDLIM2的表达虽然在癌细胞中被抑制，但在生理条件下却是高表达的。因此，基于PDLIM2的治疗将有效地缓解NF-κB介导的肿瘤发生和化疗耐药，同时保持患者体内NF-κB的生理功能(如免疫反应)的完整性。此外，靶向PDLIM2用于癌症治疗是可行的，因为我们的研究表明，抑制肿瘤细胞中PDLIM2的表达在药物上是可逆的。

DESCRIPTION (provided by applicant): Chemotherapy remains the standard first-line treatment for many cancers, including lung cancer, the leading cause of cancer deaths responsible for approximately 160,000 deaths every year in the United States alone. However, the benefits of current chemotherapy are very limited due to intrinsic and acquired resistance of cancer cells. The long-term goal of our research is to understand the mechanisms underlying tumorigenesis and chemoresistance, and to translate this understanding into novel approaches to improve cancer cure rates by establishing new effective therapies and/or priming cancer cells to respond to current therapeutic drugs. To this end, we have recently identified PDLIM2, a ubiquitously expressed PDZ-LIM domain-containing protein with the highest level in lungs, as a suppressor of lung cancer and several other cancer types such as adult T-cell leukemia/lymphoma (ATL), breast, and colon cancers. We find that the expression of PDLIM2 is epigenetically repressed in these cancer cells, and that PDLIM2 reconstitution prevents their tumorigenicity. Moreover, PDLIM2 deficiency predisposes mice to spontaneous and induced cancers, particularly lung cancer. Notably, the repression of PDLIM2 expression is associated with the chemotherapy resistance of lung cancer, and PDLIM2 re-induction is required for the epigenetic drug 5-aza-dC to induce growth inhibition and response to the chemotherapeutic drug carboplatin in multidrug resistant lung cancer cells. Mechanistic studies indicate that PDLIM2 functions as a ubiquitin E3 ligase to selectively degrade nuclear (activated) NF-κB RelA (also known as p65), a transcription factor that has been suggested to play a causative role in tumorigenesis and therapeutic resistance of multiple human cancers, including ATL, breast, colon and lung. Based on these innovative findings, we hypothesize that PDLIM2 repression leads to constitutive NFκB activation, which in turn contributes to cancer pathogenesis and therapy resistance. In this application, we aim to (1) determine the molecular mechanisms by which PDLIM2 expression is repressed in lung cancer; (2) elucidate the mechanistic role of PDLIM2 in lung cancer development; and (3) examine the role and mechanisms of PDLIM2 in lung cancer chemosensitivity and therapy. These studies are innovative and significant, because they will greatly increase our understanding of the tumorigenesis and chemoresistance of lung cancer, and may form a novel class of PDLIM2-based epigenetic approaches as a primary or adjuvant therapy for lung cancer prevention and treatment. In particular, clinical trials show that it is impractical to block NF-κB activation for cancer therapy using 'classical' NF-κB inhibitors because of the importance of NF-κB in human physiology. However, PDLIM2 prevents pathogenic but not physiological activation of NF-κB by terminating NF-κB activation. Consistently, PDLIM2 expression, although repressed in cancer cells, is high under physiological conditions. Thus, PDLIM2-based therapies will effectively alleviate NF-κB-mediated tumorigenesis and chemoresistance while keeping the physiological functions of NF-κB, such as immune responses, intact in patients. Moreover, it is feasible to target PDLIM2 for cancer therapy because our studies show that the repression of PDLIM2 expression in cancer cells is pharmacologically reversible.