Potential Therapeutic Agents Against Par-4 Target for Cancer Treatment: Where Are We Going?

Abstract

One of the greatest challenges of cancer therapeutics nowadays is to find selective targets successfully. Prostate apoptosis response-4 (Par-4) is a selective tumor suppressor protein with an interesting therapeutic potential due to its specificity on inducing apoptosis in cancer cells. Par-4 activity and levels can be downregulated in several tumors and cancer cell types, indicating poor prognosis and treatment resistance. Efforts to increase Par-4 expression levels have been studied, including its use as a therapeutic protein by transfection with adenoviral vectors or plasmids. However, gene therapy is very complex and still presents many hurdles to be overcome. We decided to review molecules and drugs with the capacity to upregulate Par-4 and, thereby, be an alternative to reach this druggable target. In addition, Par-4 localization and function are reviewed in some cancers, clarifying how it can be used as a therapeutic target.

Expression of PAWR predicts prognosis of ovarian cancer

“…Evaluating PAWR expression provided a feasible approach to predict survival and drug responsiveness of ovarian cancer patients by simply performing immunohistochemical staining, which is convenient and costeffective. Consistent with result for some other tissues [13,15], PAWR was expressed in the cytoplasm in cells of normal fallopian tubes, while there was both cytoplasmic and nuclear expression of PAWR in cancer samples. PAWR can also be secreted spontaneously by normal and cancer cells in culture [38], providing the possibility of detection by non-invasive liquid biopsy.…”

“…PRKC apoptosis WTI regulator (PAWR), also known as Par-4, is a leucine zipper domain protein implicated in various cancers, including prostate cancer, bladder cancer, breast cancer, endometrial cancer, and leukemia [8][9][10][11][12][13]. PAWR is localized in the cytoplasm of diverse normal tissue cells and in both the cytoplasm and the nucleus of many tumor cells [10].…”

Antitumor Efficacy of Arylquin 1 through Dose-Dependent Cytotoxicity, Apoptosis Induction, and Synergy with Radiotherapy in Glioblastoma Models

“…Arylquin 1, a protein known for its tumor suppression capabilities, serves as a secretagogue of prostate apoptosis response-4 (Par-4) in healthy cells [8,[19][20][21]. Par-4, which is intrinsic to normal cells, is often diminished or absent in neoplastic cells, a strategic evasion from apoptotic fate [22,23].…”

“…Par-4, which is intrinsic to normal cells, is often diminished or absent in neoplastic cells, a strategic evasion from apoptotic fate [22,23]. Suppression of Par-4 is linked to a poorer prognosis and resistance to treatment across a variety of solid tumors, underscoring its therapeutic target potential [20,24]. For instance, decreased Par-4 levels have been observed in human renal cell carcinoma and are correlated with reduced survival in patients [25][26][27].…”

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

“…Par-4 can promote the apoptosis of a variety of cancer cells. Par-4 can kill human cancer cells from pancreas 99 , cervix 100 , lung 100 , prostate 101 , kidney 101 , endometrium 102 , and colon 103 . D-2HG can inhibit the transcription of Par-4 in vitro by inhibiting promoter activity and enhancing mRNA degradation 104 .…”