By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in HRAS. Expression of MCOLN1, which encodes TRPML1, is significantly elevated in HRAS‐positive tumors and inversely correlated with patient prognosis. Concordantly, MCOLN1 knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild‐type, HRAS. Mechanistically, TRPML1 maintains oncogenic HRAS in signaling‐competent nanoclusters at the plasma membrane by mediating cholesterol de‐esterification and transport. TRPML1 inhibition disrupts the distribution and levels of cholesterol and thereby attenuates HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation. These findings reveal a selective vulnerability of HRAS‐driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.

Chronic inflammation is associated with advanced prostate cancer (PCa), although the mechanisms governing inflammation-mediated PCa progression are not fully understood. PCa progresses to an androgen independent phenotype that is incurable. We previously showed that androgen independent, androgen receptor negative (AR−) PCa cell lines have high p62/SQSTM1 levels required for cell survival. We also showed that factors in the HS-5 bone marrow stromal cell (BMSC) conditioned medium can upregulate p62 in AR+ PCa cell lines, leading us to investigate AR expression under those growth conditions. In this paper, mRNA, protein, and subcellular analyses reveal that HS-5 BMSC conditioned medium represses AR mRNA, protein, and nuclear accumulation in the C4-2 PCa cell line. Using published gene expression data, we identify the inflammatory cytokine, IL-1β, as a candidate BMSC paracrine factor to regulate AR expression and find that IL-1β is sufficient to both repress AR and upregulate p62 in multiple PCa cell lines. Immunostaining demonstrates that, while the C4-2 population shows a primarily homogeneous response to factors in HS-5 BMSC conditioned medium, IL-1β elicits a strikingly heterogeneous response; suggesting that there are other regulatory factors in the conditioned medium. Finally, while we observe concomitant AR loss and p62 upregulation in IL-1β-treated C4-2 cells, silencing of AR or p62 suggests that IL-1β regulates their protein accumulation through independent pathways. Taken together, these in vitro results suggest that IL-1β can drive PCa progression in an inflammatory microenvironment through AR repression and p62 induction to promote the development and survival of androgen independent PCa.

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Background:Cadaveric models demonstrate that failure of hip capsular repair is dependent on the robustness of the repair construct. In vivo data on capsular repair construct efficacy are limited. We investigated the effect of a figure-of-8 capsular repair on hip distraction resistance relative to native and post-capsulotomy states. We hypothesized that an unrepaired capsulotomy would demonstrate increased axial distraction compared with the native state and that capsular repair would restore distraction resistance to native levels.Methods:Patients undergoing primary hip arthroscopy by a single surgeon were prospectively enrolled between March 2020 and June 2020. Prior to any instrumentation, fluoroscopic images of the operative hip were obtained at 12.5-lbs (5.7-kg) traction intervals, up to 100 lbs (45.4 kg). Anterolateral, modified anterior, and distal anterolateral portals were established. Following interportal capsulotomy, labral repair, and osteochondroplasty, fluoroscopic images were reobtained at each traction interval. Capsular repair was performed with use of a figure-of-8 suture configuration. Traction was reapplied and fluoroscopic images were again obtained. Joint distraction distance was measured at each traction interval for all 3 capsular states. Anteroposterior pelvic radiographs were utilized to scale fluoroscopic images to obtain joint space measurements in millimeters.Results:A total of 31 hips in 31 patients were included. Capsulotomy resulted in significant increases in distraction distance from 25 (11.3 kg) to 100 lbs of traction compared with both native and capsular repair states (all comparisons, p ≤ 0.017). Capsular repair yielded a significantly greater distraction distance compared with the native state at 37.5 lbs (17.0 kg; 5.49 versus 4.98 mm, respectively; p = 0.012) and 50 lbs (22.7 kg; 6.08 versus 5.35 mm; p < 0.001). The mean difference in distraction distance between native and capsular repair states from 25 to 100 lbs of traction was 0.01 mm.Conclusions:This in vivo model demonstrates that an unrepaired interportal capsulotomy significantly increases axial distraction distance compared with the native, intact hip capsule. Performing a complete capsular closure reconstitutes resistance to axial distraction intraoperatively. Future research should evaluate the in vivo effects and associated clinical outcomes of other published capsular repair techniques and assess the durability of capsular repairs over time.

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