Multiple myeloma (MM) is a plasma cell cancer characterized by sustained endoplasmic reticulum (ER) stress and unfolded protein response activation in the setting of high rates of immunoglobulin synthesis. Consequently, MM cells rely heavily on protein quality control pathways for survival as evidenced by the clinical efficacy of proteasome inhibitors (PI). Autophagy is an intracellular self-digestion mechanism that plays a role in the ER protein quality control process. Unsurprisingly then, basal levels of autophagy were recently found to confer a survival and drug-resistance benefit to MM cells. However, excessive induction of autophagy in MM cells leads to autophagic cell death, highlighting the double-edged nature of autophagy modulation in MM. This review provides an overview of the role that autophagy plays in MM pathogenesis, survival, and drug-resistance. We highlight the potential utility of therapeutically targeting autophagy in MM, focusing on preclinical data of autophagic modulators in combination with alkylators, anthracyclines, PI, and immunomodulatory drugs.

While we made great strides in the early detection of a handful of cancers, many other cancers are still detected at fairly later stages, thus hindering the deployment of effective surgical or therapeutic intervention to change their dismal clinical outcomes. The arduous journey of cancer cells from the primary tumor to colonize distant secondary organs or tissues begins with their ability to activate or deactivate various cellular processes at will, including the autophagy machinery. In this review, we discuss how circulatory cancer cells from primary tumors could selectively mobilize different subsets of microRNAs (miRNAs) to enable autophagic recycling of nutrients during their search for secondary sites to colonize and to disable such cell survival programs once they have successfully established at distant organs or tissues. We also discuss how this new miRNA-autophagy-metastasis axis can be targeted by the emerging RNA Medicine toolkit.

Patients with glioblastoma (GBM), a malignant brain tumor, exhibit a mean survival of less than 1.5 years. Despite treatment, the disease eventually develops resistance, resulting in disease relapse. Autophagy is a process of degradation and clearance that is activated to maintain cellular homeostasis. Its roles in cancer disease course and the treatment response, however, are controversial. In GBM, accumulating evidence has indicated that autophagy can protect cells, especially those with stemness features, causing the development of cell resistance. In this review, we discuss the impact of the cell reaction to currently active treatments, including temozolomide, radiation, tumor treating fields, bevacizumab (Avastin), etoposide (VP-16), cisplatin (CDDP), and carmustine (BCNU). Most of these induce the up-regulation of autophagy through signaling pathways of DNA damage response, reactive oxygen species, hypoxia, retinoblastoma, AMP-activated protein kinase, AKT/mTOR and MST4 kinase affecting cell fate by altering cell metabolism, cell death, and DNA repair. Treatment-related autophagy may be modulated by combining autophagy inhibitors such as chloroquine or antioxidants to prevent the development of resistance, thus improving cancer treatment.

Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5’-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential “druggable” targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.

In a normal prostate, the process of controling cell death is essential to maintain tissue homeostasis and its inhibition may lead to the development of cancer. Androgen receptor signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer. The main treatment for prostate cancer is a combination of androgen deprivation therapy (ADT) using anti-androgens and docetaxil administration. However, ADT eventually fails due to a pathological unbalance of cell death processes, in particular apoptosis and autophagy. As a result prostate tumors may re-grow and progress into the castration resistant stage. The role of autophagy in tumorigenesis is complex and it could be a double-edged sword process, as autophagy defects promote cancer progression in association with various dangerous cellular processes, while functional autophagy enables cancer cell survival under stress and likely contributes to the resistance of treatment. Autophagy is often impaired in prostate cancer, due to either activation of the Akt/mTOR pathway, which normally inhibits autophagy, or through allelic loss of Beclin-1 (BECN1), an essential autophagy gene. In particular, elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and to develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.