Background: Autophagy is essential for ␤-cell function and survival. Results: Autophagic turnover is impaired in ␤-cells when treated with metabolic stressors. Conclusion: Diminished autophagy leads to apoptotic ␤-cell death. Significance: Therapeutic interventions using pharmacological agents, which can improve ER folding capacity, as well as target the autophagy machinery, could provide promising strategies for treating human diseases such as T2D.

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Cancer is one of the leading causes of death, and there is an urgent need for new biomarkers and therapeutic targets. The progesterone receptor membrane component 1 (Pgrmc1) protein is upregulated in multiple types of cancer, and Pgrmc1 is required for tumor cell proliferation, motility and tumor formation in vivo. Furthermore, a small molecule inhibitor of Pgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. Recently, Pgrmc1 was identified as the sigma‐2 receptor, a putative type of opioid receptor, and sigma‐2 receptors are induced in cancers. However, Pgrmc1 shares no homology with known opioid or hormone receptors but is related to cytochrome b5, and Pgrmc1 binds to heme and has reducing activity. In this study, we have analyzed Pgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SCLC) and lung adenocarcinomas compared to corresponding nonmalignant tissue. Pgrmc1 levels increased significantly (p ≤ 0.05) in 12/15 SCLC samples and was elevated in poorly differentiated tumors. Pgrmc1 was highly expressed in SCLC cell lines, and SCLC cell survival was inhibited by siRNA knockdown of Pgrmc1 or the Pgrmc1 inhibitor AG‐205. In adenocarcinomas, 6/15 tumors significantly had elevated Pgrmc1 levels, which correlated with patient survival. Pgrmc1 localizes to secretory vesicles in cancer cells, and Pgrmc1 was secreted by lung cancer cells. Furthermore, Pgrmc1 was significantly elevated in the plasma of lung cancer patients compared to noncancer patients. Together, the results demonstrate that Pgrmc1 is a potential tumor and serum biomarker, as well as a therapeutic target, for lung cancer.

Autophagy resembles a recycling process in which proteins, organelles, or regions of the cytoplasm are enveloped and degraded. We have found that two of the central autophagy proteins, MAP1LC3 (microtubule-associated protein 1 light chain 3, also described as LC3) and UVRAG (UV radiation resistance associated/UV radiation associated gene), complex with PGRMC1/S2R (progesterone receptor membrane component 1, also known as sigma-2 receptor). PGRMC1 is a cytochrome that is induced in cancer and is essential for tumor formation, invasion, and metastasis. Autophagy contributes to the turnover of long-lived and/or ubiquitinated proteins and the clearance of damaged organelles, and we have shown that PGRMC1 promotes both processes. Inhibition of PGRMC1 by RNAi or small molecule inhibitors causes autophagy substrates to increase and aberrant mitochondria to accumulate. We propose that this disruption of autophagy upon PGRMC1 inhibition increases AMPK activation, elevating the levels of TSC1 (tuberous sclerosis complex) and TSC2 and inactivating MTOR and RPS6KB/p70S6K, causing cleaved MAP1LC3B levels to increase. Thus, PGRMC1 binds to key components of the autophagy machinery and is required for the degradative activity of autophagy.