AMPKα-like proteins as LKB1 downstream targets in cell physiology and cancer.

One of the key events in cancer development is the ability of tumor cells to overcome nutrient deprivation and hypoxia. Among proteins performing metabolic adaptation to the various cellular nutrient conditions, liver kinase B 1 (LKB1) and its main downstream target adenosine monophosphate (AMP)-activated protein kinase α (AMPKα) are important sensors of energy requirements within the cell. Although LKB1 was originally described as a tumor suppressor, given its role in metabolism, it potentially acts as a double-edged sword. AMPKα, a master regulator of cell energy demands, is activated when ATP level drops under a certain threshold, responding accordingly through its downstream targets. Twelve downstream kinase targets of LKB1 have been described as AMPKα-like proteins. This group is comprised of novel (nua) kinase family (NUAK) kinases (NUAK1 and 2) linked to cell cycle progression and ultraviolet (UV)-damage; microtubule affinity regulating kinases (MARKs) (MARK1, MARK2, MARK3, and MARK4) that are involved in cell polarity; salt inducible kinases (SIK) (SIK1, SIK2, also known as Qin-induced kinase or QIK and SIK3) that are implicated in cell metabolism and adipose tissue development and mitotic regulation; maternal embryonic leuzine zipper kinase (MELK) that regulate oocyte maturation; and finally brain selective kinases (BRSKs) (BRSK1 and 2), which have been mainly characterized in the brain due to their role in neuronal polarization. Thus, many efforts have been made in order to harness LKB1 kinase and its downstream targets as a possible therapeutic hub in tumor development and propagation. In this review, we describe LKB1 and its downstream target AMPK summarize major functions of various AMPK-like proteins, while focusing on biological functions of BRSK1 and 2 in different models.

Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell.

Primary ovarian insufficiency (POI) is defined as a reduction in ovarian function before the expected age of menopause. POI is known to increase the risk of cardiovascular disorders, osteoporosis, cognitive decline, and mood disorders, resulting in a reduced quality of life. Appropriate hormone replacement for premenopausal women decreases these adverse health risks and improves quality of life for women with POI, but does not prolong life expectancy. The potential etiologies of POI include chromosomal abnormalities and genetic mutations, autoimmune factors, and iatrogenic causes, including surgery, chemotherapy, and radiation therapy. A major association is suggested to exist between reproductive longevity and the DNA damage pathway response genes. DNA damage and repair in ovarian granulosa cells is strongly associated with POI. Depletion of oocytes with damaged DNA occurs through different cell death mechanisms, such as apoptosis, autophagy, and necroptosis, mediated by the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/forkhead transcription factors 3 (FOXO3) pathway. Mesenchymal stem cells (MSCs) are characterized by the ability of self-renewal and differentiation and play an important role in the regeneration of injured tissues. Transplantation of MSCs has been shown to functionally restore ovarian reserve in a POI mouse model. Recent advances in stem cell therapy are likely to be translated to new therapeutic options bringing new hope to patients with POI. The aim of this review is to summarize the pathogenic mechanisms that involve cell death and DNA damage and repair pathways and to discuss the stem cell-based therapies as potential therapeutic options for this gynecologic pathology.

A decade of cell death studies: Breathing new life into necroptosis.

Programmed cell death (PCD) has been a major area of constantly growing interest over the last three decades. Originally, apoptosis was considered the only mechanistic pathway for PCD, but recently several different pathways (i.e., necroptosis, pyroptosis, ferroptosis) have emerged as important in both normal and pathological conditions. This review focuses on programmed cell necrosis (i.e., necroptosis) as a promising research direction that will help us in understanding the molecular and cellular processes behind different pathological conditions, such as chronic inflammation, neurodegeneration, and cardiovascular diseases. In addition, we discuss natural and chemical compounds and novel targeted therapies triggering necroptosis to induce cell death in cancer cells to overcome chemoresistance.